rs760741207

Positions:

• chr5-132640782-A-C
• chr5-132640782-A-G
• chr5-132640782-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005732.4(RAD50):​c.3729A>C​(p.Glu1243Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0610

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22718549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3729A>C	p.Glu1243Asp	missense_variant	24/25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132124.1	n.45+964T>G		intron_variant, non_coding_transcript_variant
TH2LCRR	NR_132125.1	n.189+1416T>G		intron_variant, non_coding_transcript_variant
TH2LCRR	NR_132126.1	n.175-2517T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3729A>C	p.Glu1243Asp	missense_variant	24/25	1	NM_005732.4	ENSP00000368100	P1
TH2LCRR	ENST00000435042.1	n.282+964T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1243 of the RAD50 protein (p.Glu1243Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 484678). 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) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 17, 2022	The p.E1243D variant (also known as c.3729A>C), located in coding exon 24 of the RAD50 gene, results from an A to C substitution at nucleotide position 3729. The glutamic acid at codon 1243 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. 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	Pathogenic	0.71
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;.;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;.;T;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;.;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.10
Sift4G	Benign	0.29	.;.;.;T
Polyphen		0.73	.;.;.;P
Vest4		0.14
MutPred		0.44		.;.;.;Loss of disorder (P = 0.1782);
MVP		0.48
ClinPred		0.82	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.63

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: rs760741207; hg19: chr5-131976474; COSMIC: COSV99529139;