rs762302203

Positions:

• chr5-132637188-T-C
• chr5-132637188-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005732.4(RAD50):​c.3463T>C​(p.Tyr1155His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3463T>C	p.Tyr1155His	missense_variant	22/25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132124.1	n.153+970A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3463T>C	p.Tyr1155His	missense_variant	22/25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.3166T>C	p.Tyr1056His	missense_variant	23/26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251442 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135896

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459532 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 726136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Oct 08, 2024

The p.Y1155H variant (also known as c.3463T>C), located in coding exon 22 of the RAD50 gene, results from a T to C substitution at nucleotide position 3463. The tyrosine at codon 1155 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;.;.;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.7	.;.;.;H
PrimateAI	Pathogenic	0.89	D
REVEL	Pathogenic	0.65
Sift4G	Pathogenic	0.0	.;.;.;D
Polyphen		1.0	.;.;.;D
Vest4		0.92
MutPred		0.76		.;.;.;Gain of disorder (P = 0.0551);
MVP		0.61
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.75
gMVP		0.95

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: rs762302203; hg19: chr5-131972880;