11-36573380-T-C

Position:

• chr11-36573380-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000448.3:c.76T>C variant in RAG1 is a missense variant predicted to cause a substitution of serine by proline at amino acid 26 (p.Ser26Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one entry without the information of the second allele, and the variant was classified as Uncertain Significance (Ambry Genetics, SCV003601680.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). LINK:https://erepo.genome.network/evrepo/ui/classification/CA380145361/MONDO:0000572/123

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 4.72

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 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAG1	NM_000448.3	c.76T>C	p.Ser26Pro	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.76T>C	p.Ser26Pro	missense_variant	2/2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Recombinase activating gene 1 deficiency Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen

Apr 23, 2024

The NM_000448.3:c.76T>C variant in RAG1 is a missense variant predicted to cause a substitution of serine by proline at amino acid 26 (p.Ser26Pro). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has not been reported in the literature in individuals with SCID. In ClinVar, the variant was reported in one entry without the information of the second allele, and the variant was classified as Uncertain Significance (Ambry Genetics, SCV003601680.1). There is no functional evidence for this variant. Due to insufficient evidence, this variant is classified as a variant of uncertain significance for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_supporting (SCID VCEP specifications version 1.0). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.76T>C (p.S26P) alteration is located in exon 2 (coding exon 1) of the RAG1 gene. This alteration results from a T to C substitution at nucleotide position 76, causing the serine (S) at amino acid position 26 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.043
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.15	T
Polyphen		0.015	B
Vest4		0.80
MutPred		0.28		Loss of MoRF binding (P = 0.0653);
MVP		0.88
MPC		0.80
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.39
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-36594930;