11-36573305-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_ModeratePM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000448.3:c.1A>G (p.Met1Val) variant in RAG1 is an initiation codon variant that is not expected to result in nonsense-mediated mRNA decay but may cause a truncated protein by using an alternative start codon (Met183). There is one frameshift variant (p.K86VfsX33) that occurs upstream of codon 183, which causes the production of an N-terminally truncated RAG1 with low recombination activity and altered cellular localization (PMIDs 24290284, 11121059, 27301863) (PVS1_Moderate). The gnomAD 2.1.1 Popmax filtering allele frequency of this variant is 0.0001017, which is lower than the SCID VCEP threshold for PM2 (0.000102), and no homozygous individual has been observed in the gnomAD. Therefore it meets this criterion (PM2_Supporting).The variant has been detected in at least four individuals diagnosed with primary immunodeficiency. Patient A, reported by PMID 26186701, was heterozygous for this variant and a p.R737H variant (not curated by the SCID-VCEP), 0 pt. The other three individuals were reported in ClinVar entries without the information of the second allele, and in all three entries, the variant was classified as Uncertain Significance (Illumina Laboratory Services, SCV000371654.2; Illumina Laboratory Services, SCV000371655.2; Invitae, SCV001230493.3). The reported patient information is not sufficient to meet PM3 or PP4 criteria. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Moderate, PM2_Supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5949886/MONDO:0000572/123

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

RAG1
NM_000448.3 start_lost

Scores

6
7
3

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:4

Conservation

PhyloP100: 4.15
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RAG1NM_000448.3 linkc.1A>G p.Met1? start_lost Exon 2 of 2 ENST00000299440.6 NP_000439.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RAG1ENST00000299440.6 linkc.1A>G p.Met1? start_lost Exon 2 of 2 1 NM_000448.3 ENSP00000299440.5 P15918-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152168
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000132
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000111
AC:
28
AN:
251374
Hom.:
0
AF XY:
0.000140
AC XY:
19
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.000153
AC:
223
AN:
1461874
Hom.:
0
Cov.:
30
AF XY:
0.000155
AC XY:
113
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000150
Gnomad4 NFE exome
AF:
0.000186
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152286
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000132
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000104
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000107
AC:
13
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:2Uncertain:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:1
Nov 26, 2021
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PM3, PS4_moderate, PVS1_moderate -

Dec 14, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Functional studies indicate that this variant may have a partial effect on mRNA expression and protein level (Geier et al., 2015); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589898, 33193364, 26186701, 31980526) -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Pathogenic:1
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the RAG1 mRNA. The next in-frame methionine is located at codon 183. This variant is present in population databases (rs200575481, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with RAG1-related disease (PMID: 26186701). ClinVar contains an entry for this variant (Variation ID: 304491). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of the initiator codon affects RAG1 function (PMID: 26186701). This variant disrupts a region of the RAG1 protein in which other variant(s) (p.Cys176Phe) have been determined to be pathogenic (PMID: 26457731, 28769923; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Recombinase activating gene 1 deficiency Uncertain:1
Oct 10, 2023
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen
Significance: Uncertain significance
Review Status: reviewed by expert panel
Collection Method: curation

The NM_000448.3:c.1A>G (p.Met1Val) variant in RAG1 is an initiation codon variant that is not expected to result in nonsense-mediated mRNA decay but may cause a truncated protein by using an alternative start codon (Met183). There is one frameshift variant (p.K86VfsX33) that occurs upstream of codon 183, which causes the production of an N-terminally truncated RAG1 with low recombination activity and altered cellular localization (PMIDs 24290284, 11121059, 27301863) (PVS1_Moderate). The gnomAD 2.1.1 Popmax filtering allele frequency of this variant is 0.0001017, which is lower than the SCID VCEP threshold for PM2 (0.000102), and no homozygous individual has been observed in the gnomAD. Therefore it meets this criterion (PM2_Supporting). The variant has been detected in at least four individuals diagnosed with primary immunodeficiency. Patient A, reported by PMID 26186701, was heterozygous for this variant and a p.R737H variant (not curated by the SCID-VCEP), 0 pt. The other three individuals were reported in ClinVar entries without the information of the second allele, and in all three entries, the variant was classified as Uncertain Significance (Illumina Laboratory Services, SCV000371654.2; Illumina Laboratory Services, SCV000371655.2; Invitae, SCV001230493.3). The reported patient information is not sufficient to meet PM3 or PP4 criteria. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PVS1_Moderate, PM2_Supporting (SCID VCEP specifications version 1.0). -

Severe combined immunodeficiency disease Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Histiocytic medullary reticulosis Uncertain:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Pathogenic
0.24
CADD
Benign
20
DANN
Uncertain
0.98
DEOGEN2
Benign
0.19
T
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.82
D
MetaSVM
Uncertain
0.11
D
PROVEAN
Benign
-0.010
N
REVEL
Uncertain
0.50
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.97
D
Vest4
0.94
MVP
0.93
ClinPred
0.73
D
GERP RS
6.1
Varity_R
0.74
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200575481; hg19: chr11-36594855; API