chr5-132642215-C-G

Variant names:

• chr5-132642215-C-G
• NM_005732.4:c.3790C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005732.4(RAD50):​c.3790C>G​(p.Leu1264Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3790C>G	p.Leu1264Val	missense_variant	Exon 25 of 25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132125.1	n.172G>C		non_coding_transcript_exon_variant	Exon 2 of 3
TH2LCRR	NR_132126.1	n.175-3950G>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3790C>G	p.Leu1264Val	missense_variant	Exon 25 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000640655.2	c.3493C>G	p.Leu1165Val	missense_variant	Exon 26 of 26	5		ENSP00000491596.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	.;.;.;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	.;.;.;H
PrimateAI	Pathogenic	0.85	D
REVEL	Uncertain	0.38
Sift4G	Uncertain	0.0090	.;.;.;D
Polyphen		1.0	.;.;.;D
Vest4		0.55
MutPred		0.60		.;.;.;Loss of stability (P = 0.2332);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.66
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-131977907;