rs397507179

chr5-132638113-G-Achr5-132638113-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_005732.4(RAD50):c.3508G>A(p.Asp1170Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1170H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• 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]

TH2LCRR (HGNC:40495): (T helper type 2 locus control region associated RNA)

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP6: Variant 5-132638113-G-A is Benign according to our data. Variant chr5-132638113-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD50	NM_005732.4	c.3508G>A	p.Asp1170Asn	missense_variant	23/25	ENST00000378823.8
TH2LCRR	NR_132124.1	n.153+45C>T		intron_variant, non_coding_transcript_variant
TH2LCRR	NR_132125.1	n.342C>T		non_coding_transcript_exon_variant	3/3
TH2LCRR	NR_132126.1	n.327C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD50	ENST00000378823.8	c.3508G>A	p.Asp1170Asn	missense_variant	23/25	1	NM_005732.4	P1
TH2LCRR	ENST00000435042.1	n.435C>T		non_coding_transcript_exon_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251392 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74310

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2023	The p.D1170N variant (also known as c.3508G>A), located in coding exon 23 of the RAD50 gene, results from a G to A substitution at nucleotide position 3508. The aspartic acid at codon 1170 is replaced by asparagine, 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. -

Nijmegen breakage syndrome-like disorder Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant classified as Uncertain significance and reported on 03-15-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 24, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.36
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	.;.;.;D
Vest4		0.87
MVP		0.58
ClinPred		0.93	D
GERP RS		6.0
Varity_R		0.33
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs397507179; hg19: chr5-131973805; COSMIC: COSV54751548;