rs587781369

Positions:

• chr5-132642282-T-A
• chr5-132642282-T-C
• chr5-132642282-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005732.4(RAD50):​c.3857T>A​(p.Phe1286Tyr) variant causes a missense change involving the alteration of a 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: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

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]

TH2LCRR (HGNC:40495): (T helper type 2 locus control region associated RNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3857T>A	p.Phe1286Tyr	missense_variant	25/25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132125.1	n.105A>T		splice_region_variant, non_coding_transcript_exon_variant	2/3
TH2LCRR	NR_132126.1	n.175-4017A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3857T>A	p.Phe1286Tyr	missense_variant	25/25	1	NM_005732.4	ENSP00000368100	P1
TH2LCRR	ENST00000435042.1	n.95A>T		splice_region_variant, non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Ambry Genetics

Sep 13, 2018

The p.F1286Y variant (also known as c.3857T>A), located in coding exon 25 of the RAD50 gene, results from a T to A substitution at nucleotide position 3857. The phenylalanine at codon 1286 is replaced by tyrosine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	.;.;.;T
Eigen	Benign	-0.054
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Benign	0.0067	T
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
REVEL	Benign	0.19
Sift4G	Benign	0.27	.;.;.;T
Polyphen		0.097	.;.;.;B
Vest4		0.62
MutPred		0.77		.;.;.;Loss of methylation at K1285 (P = 0.028);
MVP		0.51
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.26
gMVP		0.59

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

Other links and lift over

dbSNP: rs587781369; hg19: chr5-131977974;