19-50979799-T-G

Variant names:

• chr19-50979799-T-G
• NM_005046.4:c.595A>C

Variant summary

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

The NM_005046.4(KLK7):​c.595A>C​(p.Asn199His) 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: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KLK7 NM_005046.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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 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
KLK7	NM_005046.4	c.595A>C	p.Asn199His	missense_variant	Exon 5 of 6	ENST00000595820.6	NP_005037.1
KLK7	NM_139277.2	c.595A>C	p.Asn199His	missense_variant	Exon 5 of 6		NP_644806.1
KLK7	NM_001243126.1	c.574A>C	p.Asn192His	missense_variant	Exon 4 of 5		NP_001230055.1
KLK7	NM_001207053.2	c.379A>C	p.Asn127His	missense_variant	Exon 4 of 5		NP_001193982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLK7	ENST00000595820.6	c.595A>C	p.Asn199His	missense_variant	Exon 5 of 6	1	NM_005046.4	ENSP00000470538.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.05e-7 AC: 1 AN: 1418464 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 701536

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: 9.18e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.595A>C (p.N199H) alteration is located in exon 5 (coding exon 4) of the KLK7 gene. This alteration results from a A to C substitution at nucleotide position 595, causing the asparagine (N) at amino acid position 199 to be replaced by a histidine (H). 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	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.62	T;.;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.7	D;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;.;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.35
MutPred		0.63		Gain of catalytic residue at N199 (P = 0.116);Gain of catalytic residue at N199 (P = 0.116);.;
MVP		0.98
MPC		0.24
ClinPred		0.94	D
GERP RS		3.6
Varity_R		0.61
gMVP		0.78

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: chr19-51483055;