5-132640749-G-C

Variant names:

• chr5-132640749-G-C
• rs749673167
• NM_005732.4:c.3696G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005732.4(RAD50):​c.3696G>C​(p.Glu1232Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1232K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84
• 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]

ENSG00000283782 (HGNC:):

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD50	NM_005732.4	c.3696G>C	p.Glu1232Asp	missense_variant	Exon 24 of 25	ENST00000378823.8	NP_005723.2
TH2LCRR	NR_132124.1	n.45+997C>G		intron_variant	Intron 1 of 2
TH2LCRR	NR_132125.1	n.189+1449C>G		intron_variant	Intron 2 of 2
TH2LCRR	NR_132126.1	n.175-2484C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD50	ENST00000378823.8	c.3696G>C	p.Glu1232Asp	missense_variant	Exon 24 of 25	1	NM_005732.4	ENSP00000368100.4
ENSG00000283782	ENST00000638452.2	c.3399G>C	p.Glu1133Asp	missense_variant	Exon 26 of 27	5		ENSP00000492349.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	.;.;.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.3	.;.;.;M
PhyloP100		1.8
PrimateAI	Pathogenic	0.87	D
REVEL	Uncertain	0.52
Sift4G	Pathogenic	0.0	.;.;.;D
Polyphen		0.99	.;.;.;D
Vest4		0.94
MutPred		0.91		.;.;.;Loss of catalytic residue at E1232 (P = 0.0295);
MVP		0.54
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.72
gMVP		0.93
Mutation Taster		=42/58	disease causing

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: rs749673167; hg19: chr5-131976441;