17-40751284-C-A

Position:

• chr17-40751284-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.50

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 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/exons	MANE	Protein	UniProt
KRT25	NM_181534.4	c.712G>T	p.Val238Leu	missense_variant	4/8	ENST00000312150.5	NP_853512.1
KRT25	XM_011524414.2	c.706G>T	p.Val236Leu	missense_variant	5/9		XP_011522716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT25	ENST00000312150.5	c.712G>T	p.Val238Leu	missense_variant	4/8	1	NM_181534.4	ENSP00000310573	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461590 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal Recessive Hypotrichosis with Woolly Hair Pathogenic:1

Pathogenic, criteria provided, single submitter

in vitro;research

Research Centre for Medical Genetics, Research Centre for Medical Genetics

Feb 20, 2016

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

Pathogenic, no assertion criteria provided

literature only

OMIM

May 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.87		Loss of helix (P = 0.2022);
MVP		0.95
MPC		0.42
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs879253749; hg19: chr17-38907536;