Variant chr17-40748384-G-C 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_181534.4(KRT25):c.1246C>G(p.Pro416Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRT25
NM_181534.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0990

Variant links:

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]

KRT25 links:

Genome browser will be placed here

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=0.036676794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT25	NM_181534.4 linkuse as main transcript	c.1246C>G	p.Pro416Ala	missense_variant, splice_region_variant	8/8	ENST00000312150.5
KRT25	XM_011524414.2 linkuse as main transcript	c.1240C>G	p.Pro414Ala	missense_variant, splice_region_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT25	ENST00000312150.5 linkuse as main transcript	c.1246C>G	p.Pro416Ala	missense_variant, splice_region_variant	8/8	1	NM_181534.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000139

AC:

AN:

1433878

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

May 27, 2022

The c.1246C>G (p.P416A) alteration is located in exon 8 (coding exon 8) of the KRT25 gene. This alteration results from a C to G substitution at nucleotide position 1246, causing the proline (P) at amino acid position 416 to be replaced by an alanine (A). 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

0.054

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.35

CADD

Benign

3.8

DANN

Benign

0.55

DEOGEN2

Benign

0.040

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.13

M_CAP

Benign

0.026

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.26

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

REVEL

Benign

0.23

Sift

Benign

0.15

Sift4G

Benign

0.27

Polyphen

0.0030

Vest4

0.20

MutPred

0.32

Gain of MoRF binding (P = 0.0456);

MVP

0.27

MPC

0.075

ClinPred

0.058

GERP RS

-1.6

Varity_R

0.032

gMVP

0.042

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over