rs193922463

Positions:

• chr11-36576208-C-A
• chr11-36576208-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2_Supporting PM1_Supporting

This summary comes from the ClinGen Evidence Repository: NM_000448.3(RAG1):c.2904C>A is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 968 (p.Asn968Lys). This missense variant is located in the core domain (amino acids 387-1011)(PM1_Supporting). The highest population minor allele frequency in gnomAD v4 is 8.993e-7 (1/1112012 alleles) in European Non-Finnish population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient with Omenn syndrome was found heterozygous for c.3016C>G, p.N968K & c.2387C>T, p.R759C (not classified by SCID VCEP yet) (PMID:15908971):PM3 not evaluated.In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting, PM2_Supporting (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214200/MONDO:0000572/123

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:2
• Conservation: PhyloP100: 1.15

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]

RAG2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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	c.2904C>A	p.Asn968Lys	missense_variant	2/2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6	c.2904C>A	p.Asn968Lys	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Histiocytic medullary reticulosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

Recombinase activating gene 1 deficiency Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

May 07, 2024

NM_000448.3(RAG1):c.2904C>A is a missense variant predicted to cause substitution of Asparagine by Lysine at amino acid 968 (p.Asn968Lys). This missense variant is located in the core domain (amino acids 387-1011)(PM1_Supporting). The highest population minor allele frequency in gnomAD v4 is 8.993e-7 (1/1112012 alleles) in European Non-Finnish population, which is lower than the ClinGen SCID VCEP threshold (<0.000102) for PM2_Supporting, meeting this criterion (PM2_Supporting). Patient with Omenn syndrome was found heterozygous for c.3016C>G, p.N968K & c.2387C>T, p.R759C (not classified by SCID VCEP yet) (PMID: 15908971):PM3 not evaluated. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to RAG1 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM1_Supporting, PM2_Supporting (VCEP specifications version 1). -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 04, 2019

This sequence change replaces asparagine with lysine at codon 968 of the RAG1 protein (p.Asn968Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Omenn syndrome (PMID: 15908971). ClinVar contains an entry for this variant (Variation ID: 36713). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.66		Gain of methylation at N968 (P = 0.0231);
MVP		0.93
MPC		0.77
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.61
gMVP		0.84

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

Other links and lift over

dbSNP: rs193922463; hg19: chr11-36597758;