NM_000448.3:c.577G>A

Variant names:

• chr11-36573881-G-A
• rs34841221
• NM_000448.3:c.577G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS2_Supporting BA1

This summary comes from the ClinGen Evidence Repository: The c.577G>A (NM_000448.3) variant in RAG1 is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 193 (p.Glu193Lys).The filtering allele frequency (the lower threshold of the 95% CI of 772/30614) of the c.577G>A variant in RAG1 is 0.02374 for South Asian 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). 12 adult homozygous reported on GnomAD v2.1.1, BS2_Supporting is Met.In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5950009/MONDO:0000572/123

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (43 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 4.08
• 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

Our verdict: Benign. The variant received -9 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.577G>A	p.Glu193Lys	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.577G>A	p.Glu193Lys	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.577G>A	p.Glu193Lys	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.577G>A	p.Glu193Lys	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.577G>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.577G>A	p.Glu193Lys	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00385 AC: 965 AN: 250940 AF XY: 0.00467

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000327

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00196 AC: 2866 AN: 1461890 Hom.: 43 Cov.: 31 AF XY: 0.00262 AC XY: 1904 AN XY: 727246

African (AFR) AF: 0.00287 AC: 96 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0239 AC: 2064 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000339 AC: 377 AN: 1112010

Other (OTH) AF: 0.00315 AC: 190 AN: 60396

GnomAD4 genome AF: 0.00204 AC: 310 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74456

African (AFR) AF: 0.00313 AC: 130 AN: 41540

American (AMR) AF: 0.00242 AC: 37 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.0234 AC: 113 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68026

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00102 Hom.: 6

Bravo AF: 0.00143

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00412 AC: 500

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Histiocytic medullary reticulosis (1)
-	-	1	not provided (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;C2673536:Combined immunodeficiency with skin granulomas (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.059	T
Polyphen		0.025	B
Vest4		0.20
MVP		0.79
MPC		0.74
ClinPred		0.063	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.82
Mutation Taster		=86/14	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: rs34841221; hg19: chr11-36595431;