rs73455545

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000536.4(RAG2):c.-137T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 151,976 control chromosomes in the GnomAD database, including 992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 992 hom., cov: 32)

Exomes 𝑓: 0.10 ( 0 hom. )

Consequence

RAG2
NM_000536.4 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.597

Variant links:

Genes affected

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 links:

IFTAP (HGNC:25142): (intraflagellar transport associated protein) This gene encodes a protein that was identified as a cellular interacting partner of non-structural protein 10 of the severe acute respiratory syndrome coronavirus (SARS-CoV). The encoded protein may function as a negative regulator of transcription. There is a pseudogene for this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

IFTAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 11-36598211-A-G is Benign according to our data. Variant chr11-36598211-A-G is described in ClinVar as [Benign]. Clinvar id is 304561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RAG2	NM_000536.4 link	c.-137T>C	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000311485.8	NP_000527.2	P55895
RAG2	NM_000536.4 link	c.-137T>C	5_prime_UTR_variant	Exon 1 of 2	ENST00000311485.8	NP_000527.2	P55895
IFTAP	NM_138787.4 link	c.-24+3619A>G	intron_variant	Intron 1 of 5	ENST00000334307.10	NP_620142.2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
RAG2	ENST00000311485.8 link	c.-137T>C	5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	1	NM_000536.4	ENSP00000308620.4	P55895
RAG2	ENST00000311485.8 link	c.-137T>C	5_prime_UTR_variant	Exon 1 of 2	1	NM_000536.4	ENSP00000308620.4	P55895
IFTAP	ENST00000334307.10 link	c.-24+3619A>G	intron_variant	Intron 1 of 5	1	NM_138787.4	ENSP00000334848.5	Q86VG3-1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16219

AN:

151848

Hom.:

990

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.0909

Gnomad ASJ

AF:

0.102

Gnomad EAS

AF:

0.0340

Gnomad SAS

AF:

0.0767

Gnomad FIN

AF:

0.0688

Gnomad MID

AF:

0.102

Gnomad NFE

AF:

0.0964

Gnomad OTH

AF:

0.116

GnomAD4 exome

AF:

0.100

AC:

AN:

Hom.:

Cov.:

AF XY:

0.167

AC XY:

AN XY:

show subpopulations

Gnomad4 NFE exome

AF:

0.100

GnomAD4 genome

AF:

0.107

AC:

16240

AN:

151966

Hom.:

992

Cov.:

AF XY:

0.105

AC XY:

7775

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.151

Gnomad4 AMR

AF:

0.0908

Gnomad4 ASJ

AF:

0.102

Gnomad4 EAS

AF:

0.0339

Gnomad4 SAS

AF:

0.0772

Gnomad4 FIN

AF:

0.0688

Gnomad4 NFE

AF:

0.0964

Gnomad4 OTH

AF:

0.114

Alfa

AF:

0.106

Hom.:

167

Bravo

AF:

0.110

Asia WGS

AF:

0.0630

AC:

220

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Histiocytic medullary reticulosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.5

DANN

Benign

0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over