19-50980381-C-T

Variant names:

• chr19-50980381-C-T
• rs754335978
• NM_005046.4:c.328G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005046.4(KLK7):​c.328G>A​(p.Val110Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.80

Genes affected

KLK7 (HGNC:6368): (kallikrein related peptidase 7) This gene encodes a member of the kallikrein subfamily of serine proteases. These enzymes have diverse physiological functions and many kallikrein genes are biomarkers for cancer. The encoded protein has chymotrypsin-like activity and plays a role in the proteolysis of intercellular cohesive structures that precedes desquamation, the shedding of the outermost layer of the epidermis. The encoded protein may play a role in cancer invasion and metastasis, and increased expression of this gene is associated with unfavorable prognosis and progression of several types of cancer. Polymorphisms in this gene may play a role in the development of atopic dermatitis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, which is one of fifteen kallikrein subfamily members located in a gene cluster on chromosome 19. [provided by RefSeq, May 2011]

ENSG00000267879 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27381966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLK7	NM_005046.4	c.328G>A	p.Val110Ile	missense_variant	Exon 4 of 6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.328G>A	p.Val110Ile	missense_variant	Exon 4 of 6		NP_644806.1
KLK7	NM_001243126.1	c.307G>A	p.Val103Ile	missense_variant	Exon 3 of 5		NP_001230055.1
KLK7	NM_001207053.2	c.112G>A	p.Val38Ile	missense_variant	Exon 3 of 5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.328G>A	p.Val110Ile	missense_variant	Exon 4 of 6	1	NM_005046.4	ENSP00000470538.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000242

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 727224

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: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 29 AF XY: 0.0000404 AC XY: 3 AN XY: 74306

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328G>A (p.V110I) alteration is located in exon 4 (coding exon 3) of the KLK7 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the valine (V) at amino acid position 110 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.48	T;.;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.17	N;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.22	N;.;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.20	T;.;.;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		0.65	P;P;.;.
Vest4		0.13
MutPred		0.46		Loss of catalytic residue at V110 (P = 0.003);Loss of catalytic residue at V110 (P = 0.003);.;.;
MVP		0.64
MPC		0.032
ClinPred		0.36	T
GERP RS		3.6
Varity_R		0.076
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs754335978; hg19: chr19-51483637;