17-41571523-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000226.4(KRT9):​c.470T>C​(p.Met157Thr) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M157K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Consequence

KRT9
NM_000226.4 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1O:1

Conservation

PhyloP100: 6.21
Variant links:
Genes affected
KRT9 (HGNC:6447): (keratin 9) This gene encodes the type I keratin 9, an intermediate filament chain expressed only in the terminally differentiated epidermis of palms and soles. Mutations in this gene cause epidermolytic palmoplantar keratoderma. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a region_of_interest Coil 1A (size 35) in uniprot entity K1C9_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000226.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT9NM_000226.4 linkc.470T>C p.Met157Thr missense_variant Exon 1 of 8 ENST00000246662.9 NP_000217.2 P35527

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT9ENST00000246662.9 linkc.470T>C p.Met157Thr missense_variant Exon 1 of 8 1 NM_000226.4 ENSP00000246662.4 P35527
KRT9ENST00000588431.1 linkc.-189-41T>C intron_variant Intron 1 of 8 1 ENSP00000467932.1 K7EQQ3

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.00209
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Epidermolytic palmoplantar keratoderma, 1 Pathogenic:1
Jul 30, 2003
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Palmoplantar keratoderma, epidermolytic Uncertain:1
Mar 29, 2024
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Other:1
-
Epithelial Biology; Institute of Medical Biology, Singapore
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.91
D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
T
M_CAP
Pathogenic
0.43
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.88
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.99
D
Vest4
0.95
MutPred
0.96
Gain of glycosylation at M157 (P = 0.0314);
MVP
0.99
MPC
0.45
ClinPred
0.99
D
GERP RS
3.7
Varity_R
0.94
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs59510579; hg19: chr17-39727775; API