11-65881445-G-A

Position:

• chr11-65881445-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001335.4(CTSW):​c.211G>A​(p.Ala71Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTSW NM_001335.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

Genes affected

CTSW (HGNC:2546): (cathepsin W) The protein encoded by this gene, a member of the peptidase C1 family, is a cysteine proteinase that may have a specific function in the mechanism or regulation of T-cell cytolytic activity. The encoded protein is found associated with the membrane inside the endoplasmic reticulum of natural killer and cytotoxic T-cells. Expression of this gene is up-regulated by interleukin-2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTSW	NM_001335.4	c.211G>A	p.Ala71Thr	missense_variant	3/10	ENST00000307886.8	NP_001326.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSW	ENST00000307886.8	c.211G>A	p.Ala71Thr	missense_variant	3/10	1	NM_001335.4	ENSP00000311300.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458122 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725054

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.211G>A (p.A71T) alteration is located in exon 3 (coding exon 3) of the CTSW gene. This alteration results from a G to A substitution at nucleotide position 211, causing the alanine (A) at amino acid position 71 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;T;T
Eigen	Benign	0.076
Eigen_PC	Benign	0.10
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	0.55	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.22	B;P;.
Vest4		0.32
MutPred		0.37		Gain of disorder (P = 0.2078);Gain of disorder (P = 0.2078);.;
MVP		0.79
MPC		0.34
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.10
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs1860104889; hg19: chr11-65648916;