Genetic Variant KRTDAP:p.Ala38Val (chr19-35488815-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_207392.3(KRTDAP):c.113C>T(p.Ala38Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

KRTDAP
NM_207392.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.647

Variant links:

Genes affected

KRTDAP (HGNC:16313): (keratinocyte differentiation associated protein) This gene encodes a protein which may function in the regulation of keratinocyte differentiation and maintenance of stratified epithelia. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

KRTDAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025969297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTDAP	NM_207392.3 link	c.113C>T	p.Ala38Val	missense_variant	Exon 2 of 6	ENST00000338897.4	NP_997275.1	P60985-1
KRTDAP	NM_001244847.2 link	c.113C>T	p.Ala38Val	missense_variant	Exon 2 of 5		NP_001231776.1	P60985-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRTDAP	ENST00000338897.4 link	c.113C>T	p.Ala38Val	missense_variant	Exon 2 of 6	1	NM_207392.3	ENSP00000339251.3	P60985-1
KRTDAP	ENST00000484218.6 link	c.113C>T	p.Ala38Val	missense_variant	Exon 2 of 5	2		ENSP00000470713.1	P60985-2
KRTDAP	ENST00000479340.1 link	n.194C>T		non_coding_transcript_exon_variant	Exon 2 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

250964

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00104

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00103

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000680

Hom.:

Bravo

AF:

0.0000567

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113C>T (p.A38V) alteration is located in exon 2 (coding exon 2) of the KRTDAP gene. This alteration results from a C to T substitution at nucleotide position 113, causing the alanine (A) at amino acid position 38 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.21

.;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.0039

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.8

.;D

REVEL

Benign

0.010

Sift

Benign

0.18

.;T

Sift4G

Benign

0.088

T;T

Polyphen

0.014

.;B

Vest4

0.28

MutPred

0.22

Loss of relative solvent accessibility (P = 0.0404);Loss of relative solvent accessibility (P = 0.0404);

MVP

0.040

MPC

0.29

ClinPred

0.036

GERP RS

2.1

Varity_R

0.055

gMVP

0.087

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over