chr17-41586462-G-T

Variant names:

• chr17-41586462-G-T
• NM_000526.5:c.373C>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong

The NM_000526.5(KRT14):​c.373C>A​(p.Arg125Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000526.5 (KRT14) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a region_of_interest Coil 1A (size 35) in uniprot entity K1C14_HUMAN there are 17 pathogenic changes around while only 1 benign (94%) in NM_000526.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT14	NM_000526.5	c.373C>A	p.Arg125Ser	missense_variant	Exon 1 of 8	ENST00000167586.7	NP_000517.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT14	ENST00000167586.7	c.373C>A	p.Arg125Ser	missense_variant	Exon 1 of 8	1	NM_000526.5	ENSP00000167586.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epidermolysis bullosa simplex, Koebner type Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.R125S in KRT14 (NM_000526.5) causes a change at the same amino acid residue as a previously established pathogenic variant R125H. The p.R125S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R125S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 125 of KRT14 is conserved in all mammalian species. The nucleotide c.373 in KRT14 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.97		Gain of disorder (P = 0.0773);
MVP		0.99
MPC		1.5
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-39742714;