chr5-132637191-C-A

Variant names:

• chr5-132637191-C-A
• rs535261113
• NM_005732.4:c.3466C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_005732.4(RAD50):​c.3466C>A​(p.Arg1156Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R1156C) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: RAD50 NM_005732.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• 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]

ENSG00000283782 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 34 uncertain in NM_005732.4
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.3466C>A	p.Arg1156Ser	missense	Exon 22 of 25	NP_005723.2
	TH2LCRR	NR_132124.1		n.153+967G>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.3466C>A	p.Arg1156Ser	missense	Exon 22 of 25	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.3169C>A	p.Arg1057Ser	missense	Exon 24 of 27	ENSP00000492349.2
	RAD50	ENST00000533482.5	TSL:1	n.*3092C>A		non_coding_transcript_exon	Exon 22 of 25	ENSP00000431225.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152086 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74410

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.9
PrimateAI	Uncertain	0.79	T
REVEL	Benign	0.29
Sift4G	Benign	0.16	T
Polyphen		0.91	P
Vest4		0.85
MutPred		0.63		Loss of MoRF binding (P = 0.0311)
MVP		0.52
ClinPred		0.94	D
GERP RS		5.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.50
gMVP		0.92
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs535261113; hg19: chr5-131972883;