rs201069984

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000526.5(KRT14):c.88C>T(p.Arg30Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,585,378 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R30L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 21 hom. )

Consequence

KRT14
NM_000526.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2O:1

Conservation

PhyloP100: 1.08

Variant links:

Genes affected

KRT14 (HGNC:6416): (keratin 14) This gene encodes a member of the keratin family, the most diverse group of intermediate filaments. This gene product, a type I keratin, is usually found as a heterotetramer with two keratin 5 molecules, a type II keratin. Together they form the cytoskeleton of epithelial cells. Mutations in the genes for these keratins are associated with epidermolysis bullosa simplex. At least one pseudogene has been identified at 17p12-p11. [provided by RefSeq, Jul 2008]

KRT14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058447123).

BP6

Variant 17-41586747-G-A is Benign according to our data. Variant chr17-41586747-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 66381.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, not_provided=1, Uncertain_significance=1}. Variant chr17-41586747-G-A is described in Lovd as [Likely_benign]. Variant chr17-41586747-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00252 (384/152302) while in subpopulation SAS AF= 0.00807 (39/4832). AF 95% confidence interval is 0.00607. There are 1 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT14	NM_000526.5 linkuse as main transcript	c.88C>T	p.Arg30Cys	missense_variant	1/8	ENST00000167586.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT14	ENST00000167586.7 linkuse as main transcript	c.88C>T	p.Arg30Cys	missense_variant	1/8	1	NM_000526.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00253

AC:

385

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00454

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.0130

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00806

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00275

AC:

525

AN:

190686

Hom.:

AF XY:

0.00336

AC XY:

350

AN XY:

104074

show subpopulations

Gnomad AFR exome

AF:

0.00423

Gnomad AMR exome

AF:

0.000849

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00894

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00401

GnomAD4 exome

AF:

0.00168

AC:

2406

AN:

1433076

Hom.:

Cov.:

AF XY:

0.00198

AC XY:

1406

AN XY:

710880

show subpopulations

Gnomad4 AFR exome

AF:

0.00494

Gnomad4 AMR exome

AF:

0.00111

Gnomad4 ASJ exome

AF:

0.0129

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00884

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.000826

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.00252

AC:

384

AN:

152302

Hom.:

Cov.:

AF XY:

0.00265

AC XY:

197

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00452

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00807

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.00314

ESP6500AA

AF:

0.00437

AC:

ESP6500EA

AF:

0.00136

AC:

ExAC

AF:

0.00215

AC:

251

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KRT14: BS2 -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.018

Sift4G

Uncertain

0.022

Polyphen

0.071

Vest4

0.42

MVP

0.82

MPC

0.65

ClinPred

0.043

GERP RS

3.9

Varity_R

0.17

gMVP

0.74

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