rs1277380677

Variant names:

• chr5-132594876-C-A
• rs1277380677
• NM_005732.4:c.1801C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-132594876-C-A
• chr5-132594876-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005732.4(RAD50):​c.1801C>A​(p.Leu601Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. L601V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.24
• 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]

RAD50 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome-like disorder

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18316928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.1801C>A	p.Leu601Ile	missense_variant	Exon 12 of 25	ENST00000378823.8	NP_005723.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.1801C>A	p.Leu601Ile	missense_variant	Exon 12 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	c.1504C>A	p.Leu502Ile	missense_variant	Exon 14 of 27	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250068 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449114 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 721854

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33148

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100670

Other (OTH) AF: 0.00 AC: 0 AN: 59974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

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

Apr 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 484709). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with isoleucine at codon 601 of the RAD50 protein (p.Leu601Ile). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and isoleucine. 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. -

May 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L601I variant (also known as c.1801C>A), located in coding exon 12 of the RAD50 gene, results from a C to A substitution at nucleotide position 1801. The leucine at codon 601 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.10	.;.;.;T;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	.;.;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.
PhyloP100		3.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.37	.;.;.;.;N
REVEL	Benign	0.070
Sift	Benign	0.40	.;.;.;.;T
Sift4G	Benign	0.44	.;.;.;T;T
Polyphen		0.90	.;.;.;P;.
Vest4		0.62
MutPred		0.40		.;.;.;Gain of MoRF binding (P = 0.0859);.;
MVP		0.56
ClinPred		0.50	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.18
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: rs1277380677; hg19: chr5-131930568;