rs76897604

Variant names:

• chr11-36574029-A-G
• rs76897604
• NM_000448.3:c.725A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The c.725A>G, NM_000448.3, variant in RAG1 is a missense variant predicted to cause substitution of Glutamine by Arginine at amino acid 242 (p.Gln242Arg).The filtering allele frequency (the lower threshold of the 95% CI of 477/128678) of the c.725A>G variant in RAG1 is 0.003627 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold (0.00195) for BS1, and therefore meets this criterion (BS1).This variant has been detected in at least one individual with Omenn syndrome. The patient is compound heterozygous for the variant R404Q and also carries another variant in RAG1: N766I. There is no information about family segregation. Phase unknown. (PMID:32311393). No homozygous are found. This patient displays Diagnostic criteria for Omenn syndrome, which reaches 0.5pt, not enough to apply PP4 in any strength (PMID:32311393, PP4 Not_Met).In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BS1, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950037/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:9
• Conservation: PhyloP100: 0.394
• Publications: 5 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: 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.725A>G	p.Gln242Arg	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.725A>G	p.Gln242Arg	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.725A>G	p.Gln242Arg	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.725A>G	p.Gln242Arg	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.725A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.725A>G	p.Gln242Arg	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00228 AC: 571 AN: 250896 AF XY: 0.00232

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00250

Gnomad NFE exome AF: 0.00393

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00274 AC: 4011 AN: 1461874 Hom.: 8 Cov.: 31 AF XY: 0.00268 AC XY: 1950 AN XY: 727244

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

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

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86258

European-Finnish (FIN) AF: 0.00296 AC: 158 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00326 AC: 3623 AN: 1112002

Other (OTH) AF: 0.00195 AC: 118 AN: 60396

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74464

African (AFR) AF: 0.000505 AC: 21 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00243 Hom.: 2

Bravo AF: 0.00156

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00274 AC: 333

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	Recombinase activating gene 1 deficiency (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	Benign	0.053
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.038
DANN	Benign	0.38
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.78	N
PhyloP100		0.39
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MVP		0.33
MPC		0.20
ClinPred		0.0011	T
GERP RS		-1.4
Varity_R		0.025
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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: rs76897604; hg19: chr11-36595579; COSMIC: COSV104408629;