17-40751196-C-T

Variant summary

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

The NM_181534.4(KRT25):c.800G>A(p.Arg267His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,614,118 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (16 hom., cov: 32)
  • Exomes 𝑓: 0.019 (297 hom.)
• Consequence: KRT25 NM_181534.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.90

Genes affected

KRT25 (HGNC:30839): (keratin 25) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008405983).
• BP6: Variant 17-40751196-C-T is Benign according to our data. Variant chr17-40751196-C-T is described in ClinVar as [Benign]. Clinvar id is 2038746.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0144 (2188/152298) while in subpopulation NFE AF= 0.023 (1563/68012). AF 95% confidence interval is 0.022. There are 16 homozygotes in gnomad4. There are 1039 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT25	NM_181534.4	c.800G>A	p.Arg267His	missense_variant	4/8	ENST00000312150.5
KRT25	XM_011524414.2	c.794G>A	p.Arg265His	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT25	ENST00000312150.5	c.800G>A	p.Arg267His	missense_variant	4/8	1	NM_181534.4	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2188 AN: 152182 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0140 AC: 3525 AN: 251376 Hom.: 42 AF XY: 0.0137 AC XY: 1862 AN XY: 135850

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0238

Gnomad OTH exome AF: 0.0152

GnomAD4 exome AF: 0.0195 AC: 28473 AN: 1461820 Hom.: 297 Cov.: 32 AF XY: 0.0188 AC XY: 13695 AN XY: 727212

Gnomad4 AFR exome AF: 0.00355

Gnomad4 AMR exome AF: 0.00825

Gnomad4 ASJ exome AF: 0.00497

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0144 AC: 2188 AN: 152298 Hom.: 16 Cov.: 32 AF XY: 0.0140 AC XY: 1039 AN XY: 74472

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0186 Hom.: 42

Bravo AF: 0.0140

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0197 AC: 169

ExAC AF: 0.0147 AC: 1787

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0183

EpiControl AF: 0.0192

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 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0084	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.53
Sift	Benign	0.033	D
Sift4G	Uncertain	0.010	D
Polyphen		0.94	P
Vest4		0.21
MPC		0.19
ClinPred		0.029	T
GERP RS		5.8
Varity_R		0.31
gMVP		0.89

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

Other links and lift over

dbSNP: rs72821893; hg19: chr17-38907448; COSMIC: COSV56445150;