rs121912629

Variant names:

• chr5-132642364-A-T
• rs121912629
• NM_005732.4:c.3939A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM2 PM4 PP5

The NM_005732.4(RAD50):​c.3939A>T​(p.Ter1313Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002624328: Further analysis by Waltes et al. revealed a protein band of increased molecular weight consistent with this protein elongation" and additional evidence is available in ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RAD50 NM_005732.4 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 1.73
• Publications: 3 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 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002624328: Further analysis by Waltes et al. revealed a protein band of increased molecular weight consistent with this protein elongation; authors conclude that the very low amount of this larger protein was likely a result of either of protein instability or unstable nonstop mRNA. PMID:19409516
• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_005732.4 Downstream stopcodon found after 1428 codons.
• PP5: Variant 5-132642364-A-T is Pathogenic according to our data. Variant chr5-132642364-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 5873.

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.3939A>T	p.Ter1313Tyrext*?	stop_lost	Exon 25 of 25	NP_005723.2
	TH2LCRR	NR_132125.1		n.105-82T>A		intron	N/A
	TH2LCRR	NR_132126.1		n.175-4099T>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3939A>T	p.Ter1313Tyrext*?	stop_lost	Exon 25 of 25	ENSP00000368100.4	Q92878-1
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3642A>T	p.Ter1214Tyrext*?	stop_lost	Exon 27 of 27	ENSP00000492349.2	A0A1W2PQ90
	RAD50	ENST00000533482.5	TSL:1	n.*3565A>T		non_coding_transcript_exon	Exon 25 of 25	ENSP00000431225.1	E9PM98

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74378

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.74
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		1.7
Vest4		0.069
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=12/188	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121912629; hg19: chr5-131978056;