Genetic Variant KRT31:p.Ala281Ser (chr17-41395280-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002277.3(KRT31):c.841G>T(p.Ala281Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,612,992 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

KRT31
NM_002277.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.312

Variant links:

Genes affected

KRT31 (HGNC:6448): (keratin 31) The protein encoded by this gene is a member of the keratin gene family. As a type I hair keratin, it is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

KRT31 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019213587).

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT31	NM_002277.3 link	c.841G>T	p.Ala281Ser	missense_variant	Exon 5 of 7	ENST00000251645.3	NP_002268.2	Q15323

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT31	ENST00000251645.3 link	c.841G>T	p.Ala281Ser	missense_variant	Exon 5 of 7	1	NM_002277.3	ENSP00000251645.2		Q15323

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00150

Gnomad OTH

AF:

0.00288

GnomAD3 exomes

AF:

0.00113

AC:

285

AN:

251444

Hom.:

AF XY:

0.00114

AC XY:

155

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00118

AC:

1725

AN:

1460670

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

822

AN XY:

726670

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00159

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00136

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152322

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00150

Gnomad4 OTH

AF:

0.00285

Alfa

AF:

0.000833

Hom.:

Bravo

AF:

0.00147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00123

AC:

150

EpiCase

AF:

0.00153

EpiControl

AF:

0.00166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841G>T (p.A281S) alteration is located in exon 5 (coding exon 5) of the KRT31 gene. This alteration results from a G to T substitution at nucleotide position 841, causing the alanine (A) at amino acid position 281 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

0.090

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.51

M_CAP

Benign

0.036

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.0

REVEL

Benign

0.27

Sift

Benign

0.069

Sift4G

Benign

0.31

Polyphen

0.39

Vest4

0.21

MVP

0.30

MPC

0.59

ClinPred

0.024

GERP RS

5.5

Varity_R

0.22

gMVP

0.21

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