Variant 17-41477175-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002280.6(KRT35):c.1249T>A(p.Tyr417Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KRT35
NM_002280.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.490

Variant links:

Genes affected

KRT35 (HGNC:6453): (keratin 35) The protein encoded by this gene is a member of the keratin gene family. This type I hair keratin 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]

KRT35 links:

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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=0.038029313).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT35	NM_002280.6 link	c.1249T>A	p.Tyr417Asn	missense_variant	7/7	ENST00000246639.7	NP_002271.3	Q92764

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT35	ENST00000246639.7 link	c.1249T>A	p.Tyr417Asn	missense_variant	7/7	1	NM_002280.6	ENSP00000246639.3		Q92764C4AM86

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249018

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135150

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2024

The c.1249T>A (p.Y417N) alteration is located in exon 7 (coding exon 7) of the KRT35 gene. This alteration results from a T to A substitution at nucleotide position 1249, causing the tyrosine (Y) at amino acid position 417 to be replaced by an asparagine (N). 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

0.071

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.44

CADD

Benign

3.8

DANN

Benign

0.32

DEOGEN2

Benign

0.0018

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.057

T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.038

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.55

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

1.8

N;N

REVEL

Benign

0.14

Sift

Benign

0.36

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0

.;B

Vest4

0.14

MutPred

0.26

.;Loss of phosphorylation at Y417 (P = 0.0419);

MVP

0.20

MPC

0.092

ClinPred

0.043

GERP RS

2.1

Varity_R

0.043

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

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