rs4151030

Variant names:

• chr11-36574210-C-A
• rs4151030
• NM_000448.3:c.906C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-36574210-C-A
• chr11-36574210-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.906C>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause substitution of Aspartic Acid by Glutamic Acid at amino acid 302 (p.Asp302Glu).The filtering allele frequency (the lower threshold of the 95% CI of 1968/24958) of the c.906C>A variant in RAG1 is 0.07684 for African/African American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (>0.00872) for BA1, and therefore meets this criterion (BA1).In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA214206/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.022 (127 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (109 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 0.315
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
• recombinase activating gene 1 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for RAG1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	NM_000448.3	MANE Select	c.906C>A	p.Asp302Glu	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.906C>A	p.Asp302Glu	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.906C>A	p.Asp302Glu	missense	Exon 4 of 4	NP_001364207.1	P15918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.906C>A	p.Asp302Glu	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.906C>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.906C>A	p.Asp302Glu	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3357 AN: 152142 Hom.: 127 Cov.: 33

Gnomad AFR AF: 0.0763

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00617 AC: 1551 AN: 251246 AF XY: 0.00449

Gnomad AFR exome AF: 0.0805

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.00506

GnomAD4 exome AF: 0.00241 AC: 3528 AN: 1461886 Hom.: 109 Cov.: 36 AF XY: 0.00207 AC XY: 1506 AN XY: 727246

African (AFR) AF: 0.0813 AC: 2721 AN: 33480

American (AMR) AF: 0.00508 AC: 227 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53418

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1112008

Other (OTH) AF: 0.00462 AC: 279 AN: 60396

GnomAD4 genome AF: 0.0221 AC: 3362 AN: 152262 Hom.: 127 Cov.: 33 AF XY: 0.0209 AC XY: 1558 AN XY: 74446

African (AFR) AF: 0.0762 AC: 3166 AN: 41534

American (AMR) AF: 0.00954 AC: 146 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68024

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.0158 Hom.: 86

Bravo AF: 0.0249

ESP6500AA AF: 0.0752 AC: 331

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00743 AC: 902

EpiCase AF: 0.000818

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	Recombinase activating gene 1 deficiency (1)
-	-	1	Severe combined immunodeficiency disease (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C1835931:Combined immunodeficiency due to partial RAG1 deficiency;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.32
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.030	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.33		Loss of catalytic residue at N307 (P = 0.2985)
MVP		0.90
MPC		0.68
ClinPred		0.046	T
GERP RS		-0.65
Varity_R		0.64
gMVP		0.36
Mutation Taster		=85/15	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4151030; hg19: chr11-36595760;