rs1554098318

Positions:

• chr5-132589700-CTG-ATT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005732.4(RAD50):​c.1315_1317delCTGinsATT​(p.Leu439Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.60

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

ENSG00000283782 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.1315_1317delCTGinsATT	p.Leu439Ile	missense_variant		ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.1315_1317delCTGinsATT	p.Leu439Ile	missense_variant		1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.1018_1020delCTGinsATT	p.Leu340Ile	missense_variant		5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 28, 2018

This sequence change replaces leucine with isoleucine at codon 439 of the RAD50 protein (p.Leu439Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 457374). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554098318; hg19: chr5-131925392;