rs772962160

Positions:

chr11-36573559-TAA-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PVS1PP4PS3_ModeratePM3

This summary comes from the ClinGen Evidence Repository: The c.256_257del (p.Lys86ValfsTer33) variant in RAG1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. The variant causes a truncation of a functionally important region (removes amino acids 86-1011) of the RAG1 protein. The variants also cause the usage of an alternative in-frame start codon (Met183), but the alternatively transcribed protein has decreased recombination activity and mislocalization in cells (PMIDs 11121059, 27301863). So the variant may cause protein loss-of-function (PVS1; PMIDs 11121059, 27301863).The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 6/128846 observed alleles) is 0.000007030 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.000102) and therefore meets this criterion (PM2_Supporting).The in vitro recombination assay shows that the p.Lys86ValfsTer33 variant in RAG1 causes a decrease of recombination activity to below 25%, indicating that the variant impacts the protein function. (PS3_Moderate; PMID 24290284).One homozygous individual with OS. One homozygous individual with SCID. 1pt for PM3. (PMID 11121059, patient OS8; PMID 32655540, patient #32). PM3 met.One patient with this variant was diagnosed with SCID (0.5pt). The patient showed T-B-NK+ lymphocyte profile (0.5pt). 1pt in total, PP4 met. (PMID 32655540, proband #32)In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_moderate, PS3_moderate, and PP4_supporting. (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5949936/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

RAG1
NM_000448.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 4.64

Variant links:

Genes affected

RAG1 (HGNC:9831): (recombination activating 1) The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. Defects in this gene can be the cause of several diseases. [provided by RefSeq, Jul 2008]

RAG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAG1	NM_000448.3 linkuse as main transcript	c.256_257del	p.Lys86ValfsTer33	frameshift_variant	2/2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6 linkuse as main transcript	c.256_257del	p.Lys86ValfsTer33	frameshift_variant	2/2	1	NM_000448.3	ENSP00000299440	P1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

7

AN:

152142

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

3

AN:

251098

Hom.:

0

AF XY:

0.00000737

AC XY:

1

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

73

AN:

1461886

Hom.:

0

AF XY:

0.0000605

AC XY:

44

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000460

AC:

7

AN:

152142

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

0

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2015	- -

RAG1-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The RAG1 c.256_257delAA (p.Lys86ValfsTer33) variant is a frameshift variant that is predicted to result in premature termination of the protein. The p.Lys86ValfsTer33 variant has been reported in five studies in which it is found in a total of 14 individuals with RAG1-related disorders, including in eight in a homozygous state, five in a compound heterozygous state, and one in a heterozygous state (Abraham et al. 2013; Lee et al. 2014; Buchbinder et al. 2015; Walter et al. 2015; Brauer et al. 2016). Homozygous individuals included six with severe combined immune deficiency (SCID) and two with Omenn syndrome (OS); compound heterozygous individuals included two with OS, one with common variable immunodeficiency disorder (CVID), two with combined immune deficiency with granuloma and/or autoimmunity (CID-G/A); the heterozygote had an unspecified immunodeficiency. Control data are unavailable for this variant, which is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Lys86ValfsTer33 variant protein was found to have approximately three percent of wild type RAG1 recombinase activity when analyzed in pro-B cells that were deficient for wild type RAG1 (Abraham et al. 2013; Buchbinder et al. 2015; Brauer et al. 2016). Based on the evidence and potential impact of frameshift variants, the p.Lys86ValfsTer33 variant is classified as pathogenic for RAG1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 28, 2023	The RAG1 c.256_257delAA variant is predicted to result in a frameshift and premature protein termination (p.Lys86Valfs*33). This variant has been reported as causative for autosomal recessive Omenn syndrome, as well as sever combined immunodeficiency syndrome (Table 1, referred to as deletion 368-369, Villa et al. 1998. PubMed ID: 9630231; Table 2, Kutukculer et al. 2012. PubMed ID: 22424479; Sharapova et al. 2013. PubMed ID: 23085344; IJspeert et al. 2014. PubMed ID: 24418478; Buchbinder et al. 2015. PubMed ID: 25516070). It is reported to be a founder mutation in Slavic populations that originated in Poland (Sharapova et al 2020. PubMed ID: 32655540). Experimental studies indicated this variant reduces RAG1 activity compared to wildtype (referred to as c.368_369delAA, Figure 1, IJspeert et al. 2014. PubMed ID: 24418478). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-36595109-TAA-T). Frameshift variants in RAG1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Combined immunodeficiency due to partial RAG1 deficiency

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2005	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -

Recombinase activating gene 1 deficiency

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Nov 14, 2023

The c.256_257del (p.Lys86ValfsTer33) variant in RAG1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense-mediated decay. The variant causes a truncation of a functionally important region (removes amino acids 86-1011) of the RAG1 protein. The variants also cause the usage of an alternative in-frame start codon (Met183), but the alternatively transcribed protein has decreased recombination activity and mislocalization in cells (PMIDs 11121059, 27301863). So the variant may cause protein loss-of-function (PVS1; PMIDs 11121059, 27301863). The filtering allele frequency based on the European (non-Finnish) population (upper bound of 95% CI of 6/128846 observed alleles) is 0.000007030 in gnomAD v2.1.1 which is below the SCID-VCEP threshold (<0.000102) and therefore meets this criterion (PM2_Supporting). The in vitro recombination assay shows that the p.Lys86ValfsTer33 variant in RAG1 causes a decrease of recombination activity to below 25%, indicating that the variant impacts the protein function. (PS3_Moderate; PMID 24290284). One homozygous individual with OS. One homozygous individual with SCID. 1pt for PM3. (PMID 11121059, patient OS8; PMID 32655540, patient #32). PM3 met. One patient with this variant was diagnosed with SCID (0.5pt). The patient showed T-B-NK+ lymphocyte profile (0.5pt). 1pt in total, PP4 met. (PMID 32655540, proband #32) In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PVS1, PM2_supporting, PM3_moderate, PS3_moderate, and PP4_supporting. (VCEP specifications version 1). -

Severe combined immunodeficiency disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 23, 2022

Variant summary: RAG1 c.256_257delAA (p.Lys86ValfsX33) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251098 control chromosomes. c.256_257delAA has been reported in the literature in multiple individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Histiocytic medullary reticulosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2005

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

This sequence change creates a premature translational stop signal (p.Lys86Valfs*33) in the RAG1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 958 amino acid(s) of the RAG1 protein. This variant is present in population databases (rs772962160, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Omenn syndrome or severe combined immunodeficiency (PMID: 9630231, 22424479, 23085344, 24290284, 25516070). ClinVar contains an entry for this variant (Variation ID: 285045). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects RAG1 function (PMID: 10891452, 24418478, 25516070). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772962160; hg19: chr11-36595109;