Genetic Variant KRTAP4-4:p.Tyr25Cys (chr17-41160618-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032524.2(KRTAP4-4):c.74A>G(p.Tyr25Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,236 control chromosomes in the GnomAD database, including 7,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.12 ( 3713 hom., cov: 30)

Exomes 𝑓: 0.013 ( 3436 hom. )

Consequence

KRTAP4-4
NM_032524.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034354627).

BP6

Variant 17-41160618-T-C is Benign according to our data. Variant chr17-41160618-T-C is described in ClinVar as [Benign]. Clinvar id is 1239554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP4-4	NM_032524.2 link	c.74A>G	p.Tyr25Cys	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.74A>G	p.Tyr25Cys	missense_variant	Exon 1 of 1	6	NM_032524.2	ENSP00000375076.3		Q9BYR3

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18170

AN:

151338

Hom.:

3701

Cov.:

show subpopulations

Gnomad AFR

AF:

0.419

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0416

Gnomad ASJ

AF:

0.00289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00167

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.0287

Gnomad NFE

AF:

0.00186

Gnomad OTH

AF:

0.0907

GnomAD3 exomes

AF:

0.0288

AC:

7199

AN:

249896

Hom.:

1340

AF XY:

0.0222

AC XY:

3017

AN XY:

135602

show subpopulations

Gnomad AFR exome

AF:

0.416

Gnomad AMR exome

AF:

0.0203

Gnomad ASJ exome

AF:

0.00199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00101

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0130

AC:

19063

AN:

1461782

Hom.:

3436

Cov.:

AF XY:

0.0112

AC XY:

8159

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.440

Gnomad4 AMR exome

AF:

0.0231

Gnomad4 ASJ exome

AF:

0.00210

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.00114

Gnomad4 OTH exome

AF:

0.0288

GnomAD4 genome

AF:

0.120

AC:

18232

AN:

151454

Hom.:

3713

Cov.:

AF XY:

0.116

AC XY:

8616

AN XY:

74036

show subpopulations

Gnomad4 AFR

AF:

0.420

Gnomad4 AMR

AF:

0.0415

Gnomad4 ASJ

AF:

0.00289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.0000947

Gnomad4 NFE

AF:

0.00186

Gnomad4 OTH

AF:

0.0897

Alfa

AF:

0.0374

Hom.:

310

Bravo

AF:

0.140

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.373

AC:

1640

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0308

AC:

3721

EpiCase

AF:

0.00245

EpiControl

AF:

0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25363768) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.093

DEOGEN2

Benign

0.00076

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00047

LIST_S2

Benign

0.045

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-4.1

PrimateAI

Benign

0.22

PROVEAN

Benign

REVEL

Benign

0.14

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.055

MPC

0.0080

ClinPred

0.0059

GERP RS

4.6

Varity_R

0.040

gMVP

0.036

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