17-41582500-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000526.5(KRT14):c.1354G>A(p.Val452Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.02 in 1,572,222 control chromosomes in the GnomAD database, including 383 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (354 hom.)
• Consequence: KRT14 NM_000526.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.710

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002311796).
• BP6: Variant 17-41582500-C-T is Benign according to our data. Variant chr17-41582500-C-T is described in ClinVar as [Benign]. Clinvar id is 1537948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0168 (2552/152262) while in subpopulation NFE AF= 0.0232 (1576/68020). AF 95% confidence interval is 0.0222. There are 29 homozygotes in gnomad4. There are 1319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT14	NM_000526.5	c.1354G>A	p.Val452Ile	missense_variant	8/8	ENST00000167586.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT14	ENST00000167586.7	c.1354G>A	p.Val452Ile	missense_variant	8/8	1	NM_000526.5	P1
KRT14	ENST00000441550.2	n.862G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0168 AC: 2553 AN: 152144 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0496

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.0164 AC: 3033 AN: 184884 Hom.: 40 AF XY: 0.0158 AC XY: 1560 AN XY: 98470

Gnomad AFR exome AF: 0.00402

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00179

Gnomad FIN exome AF: 0.0463

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0167

GnomAD4 exome AF: 0.0203 AC: 28842 AN: 1419960 Hom.: 354 Cov.: 31 AF XY: 0.0197 AC XY: 13841 AN XY: 702314

Gnomad4 AFR exome AF: 0.00308

Gnomad4 AMR exome AF: 0.0122

Gnomad4 ASJ exome AF: 0.00434

Gnomad4 EAS exome AF: 0.0000802

Gnomad4 SAS exome AF: 0.00207

Gnomad4 FIN exome AF: 0.0458

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0168 AC: 2552 AN: 152262 Hom.: 29 Cov.: 32 AF XY: 0.0177 AC XY: 1319 AN XY: 74440

Gnomad4 AFR AF: 0.00371

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0496

Gnomad4 NFE AF: 0.0232

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0161 Hom.: 6

Bravo AF: 0.0138

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00568 AC: 25

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0113 AC: 1343

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Benign	0.083
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.28
Sift	Benign	0.13	T
Sift4G	Benign	0.16	T
Polyphen		0.10	B
Vest4		0.063
MPC		0.54
ClinPred		0.053	T
GERP RS		5.4
Varity_R		0.098
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs11551760; hg19: chr17-39738752;