chr10-113725486-G-T

Variant names:

• chr10-113725486-G-T
• rs143354631
• NM_001227.5:c.501G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001227.5(CASP7):​c.501G>T​(p.Arg167Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,936 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R167R) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CASP7 NM_001227.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.707
• Publications: 0 publications found

Genes affected

CASP7 (HGNC:1508): (caspase 7) This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. The precursor of the encoded protein is cleaved by caspase 3 and 10, is activated upon cell death stimuli and induces apoptosis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASP7	NM_001227.5	c.501G>T	p.Arg167Ser	missense_variant	Exon 5 of 7	ENST00000369318.8	NP_001218.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASP7	ENST00000369318.8	c.501G>T	p.Arg167Ser	missense_variant	Exon 5 of 7	1	NM_001227.5	ENSP00000358324.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452936 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722528

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

African (AFR) AF: 0.00 AC: 0 AN: 32738

American (AMR) AF: 0.00 AC: 0 AN: 42096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 84702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109196

Other (OTH) AF: 0.0000167 AC: 1 AN: 59938

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T;T;T;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;.;D;.;.;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.9	L;.;L;.;L;L;.;.
PhyloP100		0.71
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.7	.;D;D;.;D;D;.;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	.;D;D;.;D;D;.;D
Sift4G	Uncertain	0.027	D;D;D;T;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;D;.
Vest4		0.87
MutPred		0.57		Loss of methylation at R167 (P = 0.0346);Loss of methylation at R167 (P = 0.0346);Loss of methylation at R167 (P = 0.0346);.;Loss of methylation at R167 (P = 0.0346);Loss of methylation at R167 (P = 0.0346);.;.;
MVP		0.84
MPC		0.28
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.75
Mutation Taster		=56/44	polymorphism

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: rs143354631; hg19: chr10-115485245;