chr5-132640798-C-A

Variant names:

• chr5-132640798-C-A
• rs1230753352
• NM_005732.4:c.3745C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005732.4(RAD50):​c.3745C>A​(p.Leu1249Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1249P) has been classified 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: 0.0550
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 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.3745C>A	p.Leu1249Met	missense_variant	Exon 24 of 25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132124.1	n.45+948G>T		intron_variant	Intron 1 of 2
TH2LCRR	NR_132125.1	n.189+1400G>T		intron_variant	Intron 2 of 2
TH2LCRR	NR_132126.1	n.175-2533G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3745C>A	p.Leu1249Met	missense_variant	Exon 24 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	c.3448C>A	p.Leu1150Met	missense_variant	Exon 26 of 27	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L1249M variant (also known as c.3745C>A), located in coding exon 24 of the RAD50 gene, results from a C to A substitution at nucleotide position 3745. The leucine at codon 1249 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. 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	Uncertain	0.50
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	.;.;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;.;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.2	.;.;.;M
PhyloP100		0.055
PrimateAI	Pathogenic	0.86	D
REVEL	Benign	0.24
Sift4G	Uncertain	0.012	.;.;.;D
Polyphen		1.0	.;.;.;D
Vest4		0.38
MutPred		0.67		.;.;.;Gain of disorder (P = 0.1157);
MVP		0.58
ClinPred		0.97	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.64
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs1230753352; hg19: chr5-131976490; COSMIC: COSV99528577;