19-35488466-A-G

Variant names:

• chr19-35488466-A-G
• rs1159654323
• NM_207392.3:c.188T>C

Variant summary

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

The NM_207392.3(KRTDAP):​c.188T>C​(p.Phe63Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KRTDAP NM_207392.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22

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]

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
KRTDAP	NM_207392.3	c.188T>C	p.Phe63Ser	missense_variant	Exon 4 of 6	ENST00000338897.4	NP_997275.1
KRTDAP	NM_001244847.2	c.146T>C	p.Phe49Ser	missense_variant	Exon 3 of 5		NP_001231776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTDAP	ENST00000338897.4	c.188T>C	p.Phe63Ser	missense_variant	Exon 4 of 6	1	NM_207392.3	ENSP00000339251.3
KRTDAP	ENST00000484218.6	c.146T>C	p.Phe49Ser	missense_variant	Exon 3 of 5	2		ENSP00000470713.1
KRTDAP	ENST00000479340.1	n.269T>C		non_coding_transcript_exon_variant	Exon 4 of 6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461158 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726868

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.188T>C (p.F63S) alteration is located in exon 4 (coding exon 4) of the KRTDAP gene. This alteration results from a T to C substitution at nucleotide position 188, causing the phenylalanine (F) at amino acid position 63 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	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.065	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.0	.;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.82
MutPred		0.46		.;Gain of relative solvent accessibility (P = 0.0082);
MVP		0.21
MPC		0.94
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.56

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: rs1159654323; hg19: chr19-35979368;