chr5-132609123-G-A

Variant names:

• chr5-132609123-G-A
• rs766657227
• NM_005732.4:c.2836G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005732.4(RAD50):​c.2836G>A​(p.Asp946Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,458,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D946G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.50
• Publications: 1 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15724507).
• BP6: Variant 5-132609123-G-A is Benign according to our data. Variant chr5-132609123-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 230339.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005732.4. 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.2836G>A	p.Asp946Asn	missense	Exon 18 of 25	NP_005723.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.2836G>A	p.Asp946Asn	missense	Exon 18 of 25	ENSP00000368100.4	Q92878-1
	ENSG00000283782	ENST00000638452.2	TSL:5	c.2539G>A	p.Asp847Asn	missense	Exon 20 of 27	ENSP00000492349.2	A0A1W2PQ90
	RAD50	ENST00000533482.5	TSL:1	n.*2462G>A		non_coding_transcript_exon	Exon 18 of 25	ENSP00000431225.1	E9PM98

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247786 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

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: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1458772 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725614

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.00 AC: 0 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5210

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1110864

Other (OTH) AF: 0.0000166 AC: 1 AN: 60200

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Nijmegen breakage syndrome-like disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.5
PrimateAI	Benign	0.47	T
REVEL	Benign	0.062
Sift4G	Benign	0.27	T
Polyphen		0.029	B
Vest4		0.11
MVP		0.52
ClinPred		0.43	T
GERP RS		5.2
Varity_R		0.091
gMVP		0.13
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766657227; hg19: chr5-131944815;