dbSNP rs202087444: KRTAP5-9:p.Cys111Ser (chr11-71548988-T-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_005553.4(KRTAP5-9):c.331T>A(p.Cys111Ser) 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 1,602,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

KRTAP5-9
NM_005553.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.614

Variant links:

Genes affected

KRTAP5-9 (HGNC:23604): (keratin associated protein 5-9) Enables identical protein binding activity. Predicted to be involved in epidermis development. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP5-9 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=0.023906618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP5-9	NM_005553.4 link	c.331T>A	p.Cys111Ser	missense_variant	Exon 1 of 1	ENST00000528743.4	NP_005544.4	P26371

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRTAP5-9	ENST00000528743.4 link	c.331T>A	p.Cys111Ser	missense_variant	Exon 1 of 1	6	NM_005553.4	ENSP00000431443.3		P26371

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

148902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000988

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:

0.000353

Gnomad OTH

AF:

0.00195

GnomAD3 exomes

AF:

0.000366

AC:

AN:

251362

Hom.:

AF XY:

0.000346

AC XY:

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

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:

0.000334

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.000220

AC:

320

AN:

1453436

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

161

AN XY:

723188

show subpopulations

Gnomad4 AFR exome

AF:

0.0000314

Gnomad4 AMR exome

AF:

0.00151

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:

0.000197

Gnomad4 OTH exome

AF:

0.000569

GnomAD4 genome

AF:

0.000322

AC:

AN:

149000

Hom.:

Cov.:

AF XY:

0.000288

AC XY:

AN XY:

72854

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.000986

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00192

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000514

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000347

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.331T>A (p.C111S) alteration is located in exon 1 (coding exon 1) of the KRTAP5-9 gene. This alteration results from a T to A substitution at nucleotide position 331, causing the cysteine (C) at amino acid position 111 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

Benign

0.20

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.044

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.72

M_CAP

Benign

0.00081

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

PROVEAN

Pathogenic

-8.1

REVEL

Benign

0.068

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.016

Polyphen

0.041

Vest4

0.16

MutPred

0.36

Gain of phosphorylation at C111 (P = 0.0348);

MVP

0.36

MPC

0.12

ClinPred

0.19

GERP RS

1.3

Varity_R

0.53

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