dbSNP rs141524540: RAG1:p.Met435Val (chr11-36574607-A-G) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 17P and 1B. PS3PM1PM2PP2PP5_Very_StrongBP4

The NM_000448.3(RAG1):c.1303A>G(p.Met435Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329483: Published functional studies demonstrate that M435V only has 23.6% of WT VDJ recombination activity (PMID:24290284)" and additional evidence is available in ClinVar. The gene RAG1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

RAG1
NM_000448.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 0.929

Publications

13 publications found

Variant links:

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

RAG1 links:

Genome browser will be placed here

ACMG classification

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

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000329483: Published functional studies demonstrate that M435V only has 23.6% of WT VDJ recombination activity (PMID: 24290284); SCV001234865: Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284).; SCV002051357: The most pronounced variant effect results in 10%-<30% of normal VDJ recombination activity (example: Lee_2014). PMID: 28769923

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000448.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 0.5811 (below the threshold of 3.09). Trascript score misZ: 1.7677 (below the threshold of 3.09). GenCC associations: The gene is linked to Omenn syndrome, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, combined immunodeficiency due to partial RAG1 deficiency, immunodeficiency disease, recombinase activating gene 1 deficiency.

PP5

Variant 11-36574607-A-G is Pathogenic according to our data. Variant chr11-36574607-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18413511). . Strength limited to SUPPORTING due to the PP5.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAG1	NM_000448.3	MANE Select	c.1303A>G	p.Met435Val	missense	Exon 2 of 2	NP_000439.2	P15918-1
RAG1	NM_001377277.1		c.1303A>G	p.Met435Val	missense	Exon 5 of 5	NP_001364206.1	P15918-1
RAG1	NM_001377278.1		c.1303A>G	p.Met435Val	missense	Exon 4 of 4	NP_001364207.1	P15918-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAG1	ENST00000299440.6	TSL:1 MANE Select	c.1303A>G	p.Met435Val	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
RAG1	ENST00000534663.1	TSL:1	n.1303A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
RAG1	ENST00000697713.1		c.1303A>G	p.Met435Val	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

AN:

250804

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000710

AC:

AN:

1112012

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41470

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000173

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Combined immunodeficiency due to partial RAG1 deficiency (1)

RAG1-related disorder (1)

Severe combined immunodeficiency disease (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)

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

0.22

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.026

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.55

PhyloP100

0.93

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.75

REVEL

Uncertain

0.35

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.0

Vest4

0.29

MVP

0.87

MPC

0.19

ClinPred

0.075

GERP RS

1.6

Varity_R

0.30

gMVP

0.31

Mutation Taster

=93/7

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over