chr11-36575597-T-A

Variant names:

• chr11-36575597-T-A
• NM_000448.3:c.2293T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000448.3(RAG1):​c.2293T>A​(p.Ser765Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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]

RAG2 (HGNC:9832): (recombination activating 2) This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]

RAG2 Gene-Disease associations (from GenCC):

• Omenn syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• recombinase activating gene 2 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, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000448.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	NM_000448.3	MANE Select	c.2293T>A	p.Ser765Thr	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.2293T>A	p.Ser765Thr	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.2293T>A	p.Ser765Thr	missense	Exon 4 of 4	NP_001364207.1	P15918-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.2293T>A	p.Ser765Thr	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.2293T>A		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.2293T>A	p.Ser765Thr	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.091	D
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.71	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D
Sift4G	Benign	0.94	T
Polyphen		0.99	D
Vest4		0.11
MutPred		0.44		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.95
MPC		0.69
ClinPred		0.57	D
GERP RS		5.0
Varity_R		0.088
gMVP		0.74
Mutation Taster		=98/2	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

hg19: chr11-36597147;