dbSNP rs879253749: KRT25:p.Val238Leu (chr17-40751284-C-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_181534.4(KRT25):c.712G>T(p.Val238Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRT25
NM_181534.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.50

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_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

PP5

Variant 17-40751284-C-A is Pathogenic according to our data. Variant chr17-40751284-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 242934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-40751284-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRT25	NM_181534.4 link	c.712G>T	p.Val238Leu	missense_variant	Exon 4 of 8	ENST00000312150.5	NP_853512.1	Q7Z3Z0Q6ZPD6
KRT25	XM_011524414.2 link	c.706G>T	p.Val236Leu	missense_variant	Exon 5 of 9		XP_011522716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRT25	ENST00000312150.5 link	c.712G>T	p.Val238Leu	missense_variant	Exon 4 of 8	1	NM_181534.4	ENSP00000310573.4		Q7Z3Z0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461590

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727110

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal Recessive Hypotrichosis with Woolly Hair

Pathogenic:1

Feb 20, 2016

Research Centre for Medical Genetics, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: in vitro;research

Affected individuals demonstrated the following: • Isolated congenital WH. • Scalp hair length of approximately 5–15 cm. • Decreasing trend in follicle density from the occipital to frontotemporal scalp region from 210 to 90 cm−2, respectively (with a norm being in the range of 175–300 follicles cm−2 (Barman et al., 1965)). • Frontotemporal hairline close to normal. • Uniform hair rigidity in different scalp regions; the rate of hair growth was higher than in group 1 (individuals had a haircut every 3–4 years); • Body hair distribution was similar to that in the hypotrichosis 7 group; • Trichogram showed 25–30% hairs in telogen and 70–75% in anagen phases. • Hair light microscopy with slight dystrophic changes in the form of irregular wavy contours, along with relatively rare HS fractures and trichorrhexis nodosa. Seventy percent of hair shafts were abnormal. • Tracing of the phenotypic changing throughout the lifetime was not possible; nonetheless interviewing the members in this group suggested an absence of the hypotrichosis progression. -

Wooly hair, autosomal recessive 3

Pathogenic:1

May 24, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.5

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.86

MutPred

0.87

Loss of helix (P = 0.2022);

MVP

0.95

MPC

0.42

ClinPred

1.0

GERP RS

5.7

Varity_R

0.87

gMVP

0.73

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