17-41477069-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002280.6(KRT35):​c.1355G>A​(p.Gly452Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000772 in 1,425,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

KRT35
NM_002280.6 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65
Variant links:
Genes affected
KRT35 (HGNC:6453): (keratin 35) The protein encoded by this gene is a member of the keratin gene family. This type I hair keratin is an acidic protein which heterodimerizes with type II keratins to form hair and nails. The type I hair keratins are clustered in a region of chromosome 17q12-q21 and have the same direction of transcription. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.18662682).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT35NM_002280.6 linkc.1355G>A p.Gly452Glu missense_variant Exon 7 of 7 ENST00000246639.7 NP_002271.3 Q92764

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT35ENST00000246639.7 linkc.1355G>A p.Gly452Glu missense_variant Exon 7 of 7 1 NM_002280.6 ENSP00000246639.3 Q92764C4AM86

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.0000186
AC:
4
AN:
214884
Hom.:
0
AF XY:
0.0000344
AC XY:
4
AN XY:
116400
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000120
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000199
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000772
AC:
11
AN:
1425234
Hom.:
0
Cov.:
48
AF XY:
0.0000127
AC XY:
9
AN XY:
707386
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000507
Gnomad4 SAS exome
AF:
0.0000125
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000729
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34
ExAC
AF:
0.0000166
AC:
2

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 10, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1355G>A (p.G452E) alteration is located in exon 7 (coding exon 7) of the KRT35 gene. This alteration results from a G to A substitution at nucleotide position 1355, causing the glycine (G) at amino acid position 452 to be replaced by a glutamic acid (E). 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
0.13
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.14
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0067
T;T
Eigen
Uncertain
0.20
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.19
T;T
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Uncertain
2.1
.;M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
0.44
N;N
REVEL
Uncertain
0.38
Sift
Benign
0.045
D;D
Sift4G
Benign
0.069
T;T
Polyphen
0.54
.;P
Vest4
0.22
MutPred
0.25
.;Gain of solvent accessibility (P = 0.0456);
MVP
0.56
MPC
0.13
ClinPred
0.70
D
GERP RS
5.4
Varity_R
0.11
gMVP
0.59

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: rs777526892; hg19: chr17-39633321; API