rs1554944877

Variant names:

• chr11-36574536-T-C
• rs1554944877
• NM_000448.3:c.1232T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000448.3(RAG1):​c.1232T>C​(p.Leu411Pro) 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, single submitter P: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 Likely_pathogenic. Variant got 8 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, 0.936
• PP5: Variant 11-36574536-T-C is Pathogenic according to our data. Variant chr11-36574536-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 469111.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_000448.3	c.1232T>C	p.Leu411Pro	missense_variant	Exon 2 of 2	ENST00000299440.6	NP_000439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAG1	ENST00000299440.6	c.1232T>C	p.Leu411Pro	missense_variant	Exon 2 of 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:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 03, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Experimental studies have shown that this missense change demonstrates disrupted recombination activity (PMID: 24290284, 24817258). 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. Experimental studies have shown that this missense change demonstrates disrupted recombination activity (PMID: 24290284, 24817258). This variant has been observed in individual(s) with severe combined immunodeficiency or Omenn syndrome with RAG1 reversion mosaicism (PMID: 24290284, 24817258). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 411 of the RAG1 protein (p.Leu411Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.66		Loss of stability (P = 0.0145);
MVP		0.98
MPC		0.95
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.88

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: rs1554944877; hg19: chr11-36596086;