rs139113046

Variant names:

• chr11-36576320-A-G
• rs139113046
• NM_000448.3:c.3016A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_000448.3(RAG1):​c.3016A>G​(p.Met1006Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,614,136 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 8.87
• Publications: 12 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: Benign. The variant received -8 ACMG points.

• 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=0.014743745).
• BP6: Variant 11-36576320-A-G is Benign according to our data. Variant chr11-36576320-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 536963.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.3016A>G	p.Met1006Val	missense	Exon 2 of 2	NP_000439.2	P15918-1
	RAG1	NM_001377277.1		c.3016A>G	p.Met1006Val	missense	Exon 5 of 5	NP_001364206.1	P15918-1
	RAG1	NM_001377278.1		c.3016A>G	p.Met1006Val	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.3016A>G	p.Met1006Val	missense	Exon 2 of 2	ENSP00000299440.5	P15918-1
	RAG1	ENST00000534663.1	TSL:1	n.2789+227A>G		intron	N/A	ENSP00000434610.1	P15918-2
	RAG1	ENST00000697713.1		c.3016A>G	p.Met1006Val	missense	Exon 3 of 3	ENSP00000513411.1	P15918-1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152216 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00716

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00188 AC: 470 AN: 250170 AF XY: 0.00190

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00661

Gnomad NFE exome AF: 0.00227

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00194 AC: 2830 AN: 1461802 Hom.: 5 Cov.: 33 AF XY: 0.00194 AC XY: 1414 AN XY: 727198

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00129 AC: 111 AN: 86258

European-Finnish (FIN) AF: 0.00778 AC: 415 AN: 53334

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00193 AC: 2146 AN: 1112008

Other (OTH) AF: 0.00207 AC: 125 AN: 60396

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152334 Hom.: 1 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74492

African (AFR) AF: 0.000313 AC: 13 AN: 41580

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00716 AC: 76 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00157 Hom.: 0

Bravo AF: 0.000960

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Histiocytic medullary reticulosis (1)
-	-	1	not specified (1)
-	-	1	RAG1-related disorder (1)
-	1	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive (1)
-	-	1	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas (1)
-	1	-	Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	0.0097	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.080	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.61	P
Vest4		0.73
MVP		0.93
MPC		0.34
ClinPred		0.082	T
GERP RS		5.6
Varity_R		0.68
gMVP		0.61
Mutation Taster		=72/28	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: rs139113046; hg19: chr11-36597870;