5-132575863-G-C

Variant names:

• chr5-132575863-G-C
• rs757638011
• ENST00000638452.2:c.3G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000416135.5(RAD50):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RAD50 ENST00000416135.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.58
• Publications: 1 publications found

Genes affected

ENSG00000283782 (HGNC:):

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 41 codons. Genomic position: 132579369. Lost 0.403 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000416135.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.300G>C	p.Met100Ile	missense	Exon 3 of 25	NP_005723.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3G>C	p.Met1?	start_lost	Exon 5 of 27	ENSP00000492349.2	A0A1W2PQ90
	RAD50	ENST00000416135.5	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 3 of 5	ENSP00000389515.1	C9JNH8
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.300G>C	p.Met100Ile	missense	Exon 3 of 25	ENSP00000368100.4	Q92878-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251324 AF XY: 0.00000736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

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: 6.87e-7 AC: 1 AN: 1455676 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724652

African (AFR) AF: 0.0000300 AC: 1 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106396

Other (OTH) AF: 0.00 AC: 0 AN: 60186

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.056	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.6	L
PhyloP100		9.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.32
Sift	Benign	0.047	D
Sift4G	Benign	0.068	T
Polyphen		0.94	P
Vest4		0.67
MutPred		0.56		Loss of catalytic residue at V96 (P = 0.0842)
MVP		0.72
ClinPred		0.61	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.55
Mutation Taster		=247/53	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: rs757638011; hg19: chr5-131911555;