rs199474677

Positions:

• chr11-36574665-T-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000448.3(RAG1):​c.1361T>A​(p.Leu454Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a DNA_binding_region NBD (size 67) in uniprot entity RAG1_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000448.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 11-36574665-T-A is Pathogenic according to our data. Variant chr11-36574665-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-36574665-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAG1	NM_000448.3	c.1361T>A	p.Leu454Gln	missense_variant	2/2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6	c.1361T>A	p.Leu454Gln	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2023	Published functional studies suggest a damaging effect on recombination activity (Lee et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21624848, 24290284, 29051008, 34664192, 15242397, 19396172, 26996199, 11971977, 27825771, 32311393, 35487367) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 454 of the RAG1 protein (p.Leu454Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Omenn syndrome and/or severe combined immunodeficiency (PMID: 21624848, 34664192). ClinVar contains an entry for this variant (Variation ID: 68682). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.57		Gain of disorder (P = 0.0186);
MVP		0.97
MPC		0.75
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.70
gMVP		0.81

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: rs199474677; hg19: chr11-36596215;