Genetic Variant KRTAP4-4:p.Cys71Phe (chr17-41160480-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032524.2(KRTAP4-4):c.212G>T(p.Cys71Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,611,080 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000094 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

KRTAP4-4
NM_032524.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.769

Variant links:

Genes affected

KRTAP4-4 (HGNC:16928): (keratin associated protein 4-4) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the ultrahigh sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

KRTAP4-4 links:

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ACMG classification

Classification made for transcript

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=0.27670017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-4	NM_032524.2 link	c.212G>T	p.Cys71Phe	missense_variant	Exon 1 of 1	ENST00000390661.5	NP_115913.1	Q9BYR3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP4-4	ENST00000390661.5 link	c.212G>T	p.Cys71Phe	missense_variant	Exon 1 of 1	6	NM_032524.2	ENSP00000375076.3		Q9BYR3

Frequencies

GnomAD3 genomes

AF:

0.0000935

AC:

AN:

149716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000124

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:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

249594

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

135494

show subpopulations

Gnomad AFR exome

AF:

0.000196

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:

0.000195

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000244

AC:

357

AN:

1461364

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000312

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000935

AC:

AN:

149716

Hom.:

Cov.:

AF XY:

0.0000821

AC XY:

AN XY:

73116

show subpopulations

Gnomad4 AFR

AF:

0.000124

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:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000240

Hom.:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.212G>T (p.C71F) alteration is located in exon 1 (coding exon 1) of the KRTAP4-4 gene. This alteration results from a G to T substitution at nucleotide position 212, causing the cysteine (C) at amino acid position 71 to be replaced by a phenylalanine (F). 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

0.22

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.045

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.53

M_CAP

Benign

0.0026

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.98

MutationAssessor

Pathogenic

4.7

PrimateAI

Benign

0.24

PROVEAN

Pathogenic

-8.9

REVEL

Benign

0.090

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.21

MVP

0.30

MPC

0.0077

ClinPred

0.34

GERP RS

4.0

Varity_R

0.43

gMVP

0.064

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