chr19-50980333-A-G

Position:

• chr19-50980333-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005046.4(KLK7):​c.376T>C​(p.Ser126Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.17

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10664126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KLK7	NM_005046.4	c.376T>C	p.Ser126Pro	missense_variant	4/6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.376T>C	p.Ser126Pro	missense_variant	4/6		NP_644806.1
KLK7	NM_001243126.1	c.355T>C	p.Ser119Pro	missense_variant	3/5		NP_001230055.1
KLK7	NM_001207053.2	c.160T>C	p.Ser54Pro	missense_variant	3/5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.376T>C	p.Ser126Pro	missense_variant	4/6	1	NM_005046.4	ENSP00000470538	P1
	ENST00000594512.1	n.297+7000A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

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.: 29

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

Nov 27, 2023

The c.376T>C (p.S126P) alteration is located in exon 4 (coding exon 3) of the KLK7 gene. This alteration results from a T to C substitution at nucleotide position 376, causing the serine (S) at amino acid position 126 to be replaced by a proline (P). 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	0.079
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.57
DANN	Benign	0.62
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.31	T;.;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.74	N;.;.;.
REVEL	Benign	0.11
Sift	Benign	0.63	T;.;.;.
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.21
MutPred		0.41		Loss of phosphorylation at S126 (P = 0.0335);Loss of phosphorylation at S126 (P = 0.0335);.;.;
MVP		0.80
MPC		0.035
ClinPred		0.031	T
GERP RS		-7.7
Varity_R		0.39
gMVP		0.60

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: rs1294731696; hg19: chr19-51483589;