9-97035594-C-A

Variant names:

• chr9-97035594-C-A
• NM_001333.4:c.721G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001333.4(CTSV):​c.721G>T​(p.Ala241Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A241T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTSV NM_001333.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

Genes affected

CTSV (HGNC:2538): (cathepsin V) The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine proteinase that may play an important role in corneal physiology. This gene is expressed in colorectal and breast carcinomas but not in normal colon, mammary gland, or peritumoral tissues, suggesting a possible role for this gene in tumor processes. Alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSV	NM_001333.4	c.721G>T	p.Ala241Ser	missense_variant	Exon 6 of 8	ENST00000259470.6	NP_001324.2
CTSV	NM_001201575.2	c.721G>T	p.Ala241Ser	missense_variant	Exon 6 of 8		NP_001188504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSV	ENST00000259470.6	c.721G>T	p.Ala241Ser	missense_variant	Exon 6 of 8	1	NM_001333.4	ENSP00000259470.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.721G>T (p.A241S) alteration is located in exon 6 (coding exon 5) of the CTSV gene. This alteration results from a G to T substitution at nucleotide position 721, causing the alanine (A) at amino acid position 241 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Benign	0.0090	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;D
Vest4		0.61
MutPred		0.81		Gain of disorder (P = 0.079);Gain of disorder (P = 0.079);
MVP		0.83
MPC		0.45
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.75
gMVP		0.76

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-99797876;