5-132638113-G-C

Variant names:

• chr5-132638113-G-C
• NM_005732.4:c.3508G>C

Variant summary

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

The NM_005732.4(RAD50):​c.3508G>C​(p.Asp1170His) 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60

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:):

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 rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3508G>C	p.Asp1170His	missense_variant	Exon 23 of 25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132125.1	n.342C>G		non_coding_transcript_exon_variant	Exon 3 of 3
TH2LCRR	NR_132126.1	n.327C>G		non_coding_transcript_exon_variant	Exon 2 of 2
TH2LCRR	NR_132124.1	n.153+45C>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3508G>C	p.Asp1170His	missense_variant	Exon 23 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.3211G>C	p.Asp1071His	missense_variant	Exon 24 of 26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Oct 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1170 of the RAD50 protein (p.Asp1170His). 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: 1502972). 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 expected to disrupt RAD50 protein function with a positive predictive value of 80%. 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. -

Mar 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1170H variant (also known as c.3508G>C), located in coding exon 23 of the RAD50 gene, results from a G to C substitution at nucleotide position 3508. The aspartic acid at codon 1170 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	.;.;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.8	.;.;.;M
PrimateAI	Pathogenic	0.88	D
REVEL	Uncertain	0.42
Sift4G	Uncertain	0.0030	.;.;.;D
Polyphen		1.0	.;.;.;D
Vest4		0.88
MutPred		0.48		.;.;.;Loss of stability (P = 0.05);
MVP		0.61
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-131973805;