17-40822137-A-G

Position:

• chr17-40822137-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000421.5(KRT10):​c.449T>C​(p.Met150Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M150R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KRT10 NM_000421.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.45

Genes affected

KRT10 (HGNC:6413): (keratin 10) This gene encodes a member of the type I (acidic) cytokeratin 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. Mutations in this gene are associated with epidermolytic hyperkeratosis. This gene is located within a cluster of keratin family members on chromosome 17q21. [provided by RefSeq, Jul 2008]

KRT10-AS1 (HGNC:28305): (KRT10 antisense RNA 1) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000421.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-40822137-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 14577.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-40822137-A-G is Pathogenic according to our data. Variant chr17-40822137-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-40822137-A-G is described in Lovd as [Pathogenic]. Variant chr17-40822137-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT10	NM_000421.5	c.449T>C	p.Met150Thr	missense_variant	1/8	ENST00000269576.6
KRT10-AS1	NR_160888.1	n.64+2929A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT10	ENST00000269576.6	c.449T>C	p.Met150Thr	missense_variant	1/8	1	NM_000421.5	P2
KRT10-AS1	ENST00000301665.9	n.108+2929A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met150 amino acid residue in KRT10. Other variant(s) that disrupt this residue have been observed in individuals with KRT10-related conditions (PMID: 21271994), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KRT10 protein function. ClinVar contains an entry for this variant (Variation ID: 14579). This missense change has been observed in individual(s) with autosomal dominant KRT10-related conditions (PMID: 7526210, 14705805, 15583602, 21271994). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 150 of the KRT10 protein (p.Met150Thr). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2016	The M150T variant has been reported previously in patients with epidermolytic hyperkeratosis, including as a de novo finding (Paller et al., 1994; Akiyama et al., 2003; Arin et al., 2011). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. M150T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within a known mutational hotspot region (helix initiation motif) that is highly conserved across all species and among all members of the keratin family. Many other pathogenic variants in patients with epidermolytic ichthyosis have been reported at the same (M150R) and in nearby residues (Q151P, L153/V, N154H) according to the Human Gene Mutation Database (Stenson et al., 2014). It is well established that keratin gene mutations affecting the residues at the ends of the central rod domains of the keratin proteins (helix initiation and termination motifs) interfere with proper keratin intermediate filament assembly and function, resulting in skin fragility and/or hyperkeratosis (Chamcheu et al., 2011). Therefore, M150T is pathogenic and consistent with a diagnosis of epidermolytic ichthyosis (EI, also known as epidermolytic hyperkeratosis or EHK). Of note, epidermolytic ichthyosis in most patients with a pathogenic KRT10 variant seems to spare the skin of palms and soles (none or very mild palmoplantar keratoderma). -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Epidermolytic hyperkeratosis 2A, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 24, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.96		Gain of glycosylation at M150 (P = 0.0338);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

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: rs58901407; hg19: chr17-38978389; COSMIC: COSV54091035; COSMIC: COSV54091035;