11-36574823-C-T

Variant names:

• chr11-36574823-C-T
• rs104894298
• NM_000448.3:c.1519C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_000448.3(RAG1):​c.1519C>T​(p.Arg507Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R507Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: RAG1 NM_000448.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 4.53
• 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]

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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-36574824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 973663.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-36574823-C-T is Pathogenic according to our data. Variant chr11-36574823-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242791.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	NM_000448.3	MANE Select	c.1519C>T	p.Arg507Trp	missense	Exon 2 of 2	NP_000439.2
	RAG1	NM_001377277.1		c.1519C>T	p.Arg507Trp	missense	Exon 5 of 5	NP_001364206.1
	RAG1	NM_001377278.1		c.1519C>T	p.Arg507Trp	missense	Exon 4 of 4	NP_001364207.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAG1	ENST00000299440.6	TSL:1 MANE Select	c.1519C>T	p.Arg507Trp	missense	Exon 2 of 2	ENSP00000299440.5
	RAG1	ENST00000534663.1	TSL:1	n.1519C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000434610.1
	RAG1	ENST00000697713.1		c.1519C>T	p.Arg507Trp	missense	Exon 3 of 3	ENSP00000513411.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251076 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461890 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000188 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive;C1835931:Combined immunodeficiency due to partial RAG1 deficiency;C2673536:Combined immunodeficiency with skin granulomas;C2700553:Histiocytic medullary reticulosis Pathogenic:1

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 507 of the RAG1 protein (p.Arg507Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency and Omenn syndrome (PMID: 11133745, 18463379, 28769923). ClinVar contains an entry for this variant (Variation ID: 242791). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAG1 protein function. Experimental studies have shown that this missense change affects RAG1 function (PMID: 24290284). 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.

not specified Uncertain:1

Oct 27, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RAG1 c.1519C>T (p.Arg507Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251076 control chromosomes. c.1519C>T has been reported in the literature as a compound heterozygous genotype in at-least two individuals with features of atypical Severe Combined Immunodeficiency Syndrome/Omenn Syndrome (SCID/OS) (example, Villa_2001, Schuetz_2008). One of these reported cases harbored this variant in cis with p.Arg737His on the paternal allele while the maternal allele harbored a different variant (p.Arg314Trp) (Schuetz_2008) and this individual has subsequently been cited by others (example, Schuetz_2014, Lee_2014, Farmer_2019). The presence of this complex allele representation makes it challenging to capture the impact of this variant in isolation. Therefore, only one report of its presence as a presumed compound heterozygous genotype with p.Arg561Cys in an individual affected with atypical SCID/OS is captured in the context of this evaluation (Villa_2001). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in isolation (Lee_2014). The most pronounced variant effect results in approximately 16% of normal RAG recombinase activity in-vitro. In another study, the paternally derived complex allele is reported as having 0.09 or 3% of WT activity while the maternal p.Arg314Trp allele had an activity of 0.96 or 30% of WT (Schuetz_2008) in-vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.94		Gain of ubiquitination at K511 (P = 0.0416)
MVP		0.92
MPC		0.75
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.82
Mutation Taster		=19/81	disease causing

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: rs104894298; hg19: chr11-36596373;