rs772340017

chr11-36574742-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000448.3(RAG1):c.1438A>G(p.Ser480Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S480S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 11-36574742-A-G is Pathogenic according to our data. Variant chr11-36574742-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191017.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAG1	NM_000448.3	c.1438A>G	p.Ser480Gly	missense_variant	2/2	ENST00000299440.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAG1	ENST00000299440.6	c.1438A>G	p.Ser480Gly	missense_variant	2/2	1	NM_000448.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251122 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135718

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461884 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 28, 2024

Variant summary: RAG1 c.1438A>G (p.Ser480Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251122 control chromosomes. c.1438A>G has been reported in the literature at a homozygous state in at-least two individuals affected with Severe Combined Immunodeficiency (Monies_2019, Schuetz_2023, Schuetz_2014). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 55% of normal V(D)J recombination activity in human primary dermal fibroblasts (Schuetz_2023, Schuetz_2014). The following publications have been ascertained in the context of this evaluation (PMID: 31130284, 36279417, 24331380). ClinVar contains an entry for this variant (Variation ID: 191017). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

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- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 19, 2021

This variant has been observed in individual(s) with clinical features of RAG1-related conditions (PMID: 24331380, 31130284). This variant is present in population databases (rs772340017, ExAC 0.001%). This sequence change replaces serine with glycine at codon 480 of the RAG1 protein (p.Ser480Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. ClinVar contains an entry for this variant (Variation ID: 191017). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAG1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.97	D
Vest4		0.89
MutPred		0.64		Gain of MoRF binding (P = 0.1357);
MVP		0.96
MPC		0.63
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.70

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

Other links and lift over

dbSNP: rs772340017; hg19: chr11-36596292;