rs4151031

chr11-36574650-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000448.3(RAG1):c.1346G>A(p.Arg449Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0149 in 1,614,222 control chromosomes in the GnomAD database, including 207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.010 (17 hom., cov: 33)
  • Exomes 𝑓: 0.015 (190 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 4.40

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a DNA_binding_region NBD (size 67) in uniprot entity RAG1_HUMAN there are 31 pathogenic changes around while only 3 benign (91%) in NM_000448.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.009579271).
• BP6: Variant 11-36574650-G-A is Benign according to our data. Variant chr11-36574650-G-A is described in ClinVar as [Benign]. Clinvar id is 256188.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-36574650-G-A is described in Lovd as [Likely_benign]. Variant chr11-36574650-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1553/152342) while in subpopulation NFE AF= 0.0167 (1135/68022). AF 95% confidence interval is 0.0159. There are 17 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG1	NM_000448.3	c.1346G>A	p.Arg449Lys	missense_variant	2/2	ENST00000299440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG1	ENST00000299440.6	c.1346G>A	p.Arg449Lys	missense_variant	2/2	1	NM_000448.3	P1

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1554 AN: 152224 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0527

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00975 AC: 2446 AN: 250856 Hom.: 20 AF XY: 0.00963 AC XY: 1306 AN XY: 135560

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.0154 AC: 22480 AN: 1461880 Hom.: 190 Cov.: 36 AF XY: 0.0149 AC XY: 10859 AN XY: 727242

Gnomad4 AFR exome AF: 0.00242

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00123

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.0102 AC: 1553 AN: 152342 Hom.: 17 Cov.: 33 AF XY: 0.00949 AC XY: 707 AN XY: 74496

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.0135 Hom.: 33

Bravo AF: 0.0100

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.0104 AC: 1266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0145

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 24290284, 21228398, 16960852, 27609655, 33046446) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	RAG1: PM5, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 11, 2019	Variant summary: RAG1 c.1346G>A (p.Arg449Lys) results in a conservative amino acid change located in the RAG nonamer-binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0098 in 250856 control chromosomes, predominantly at a frequency of 0.017 within the Non-Finnish European subpopulation in the gnomAD database, including 20 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 24-folds over the estimated maximal expected allele frequency for a pathogenic variant in RAG1 causing Severe Combined Immunodeficiency Syndrome/Omenn Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1346G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (Haq_2007, Sobacchi_2006, Lee_2014, Kumanovics_2017). These reports do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome/Omenn Syndrome. Co-occurrences with RAG1 pathogenic variants in cis have been reported (R404Q and R410Q), providing supporting evidence for a benign role. Functional study, Lee_2014, found the variant to have comparable levels to wild type for recombination activity. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Histiocytic medullary reticulosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Recombinase activating gene 1 deficiency Benign:1

Benign, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Jan 23, 2024

The NM_000448.3:c.1346G>A variant in RAG1 is a missense variant predicted to cause the substitution of Arginine by Lysine at amino acid 449 (p.Arg449Lys). The filtering allele frequency (the lower threshold of the 95% CI of 21803/1180030) of the c.1346G>A variant in RAG1 is 0.01837 for European (non-Finnish) chromosomes by gnomAD v.4, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1 and, therefore, meets this criterion (BA1). Additionally, 207 homozygous adults are reported on gnomAD v.4 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: BA1 and BS2_Supporting. (VCEP specifications version 1). -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.048	D
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.091
MPC		0.62
ClinPred		0.052	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.49

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: rs4151031; hg19: chr11-36596200; COSMIC: COSV104408609; COSMIC: COSV104408609;