11-36573881-G-C

Variant names:

• chr11-36573881-G-C
• rs34841221
• NM_000448.3:c.577G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000448.3(RAG1):​c.577G>C​(p.Glu193Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E193K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• Publications: 0 publications found

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]

RAG1 Gene-Disease associations (from GenCC):

• immunodeficiency disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• recombinase activating gene 1 deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• combined immunodeficiency due to partial RAG1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 59 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 0.5811 (below the threshold of 3.09). Trascript score misZ: 1.7677 (below the threshold of 3.09). GenCC associations: The gene is linked to combined immunodeficiency due to partial RAG1 deficiency, severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive, Omenn syndrome, recombinase activating gene 1 deficiency, immunodeficiency disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30284578).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAG1	NM_000448.3	c.577G>C	p.Glu193Gln	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.577G>C	p.Glu193Gln	missense_variant	Exon 2 of 2	1	NM_000448.3	ENSP00000299440.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.10	T
Sift4G	Uncertain	0.048	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.57		Gain of catalytic residue at E193 (P = 0.1382);
MVP		0.79
MPC		0.71
ClinPred		0.52	D
GERP RS		5.0
Varity_R		0.075
gMVP		0.77
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs34841221; hg19: chr11-36595431;