17-41477127-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_002280.6(KRT35):​c.1297G>A​(p.Gly433Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,612,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

KRT35
NM_002280.6 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.493
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 Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.011295497).
BP6
Variant 17-41477127-C-T is Benign according to our data. Variant chr17-41477127-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2394052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT35NM_002280.6 linkc.1297G>A p.Gly433Ser 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.1297G>A p.Gly433Ser missense_variant Exon 7 of 7 1 NM_002280.6 ENSP00000246639.3 Q92764C4AM86

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000507
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000564
AC:
14
AN:
248108
Hom.:
0
AF XY:
0.0000371
AC XY:
5
AN XY:
134676
show subpopulations
Gnomad AFR exome
AF:
0.000776
Gnomad AMR exome
AF:
0.0000583
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000370
AC:
54
AN:
1460500
Hom.:
0
Cov.:
35
AF XY:
0.0000289
AC XY:
21
AN XY:
726572
show subpopulations
Gnomad4 AFR exome
AF:
0.000717
Gnomad4 AMR exome
AF:
0.0000449
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000234
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.000148
AC XY:
11
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.000507
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000129
Hom.:
0
Bravo
AF:
0.000223
ESP6500AA
AF:
0.00102
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000827
AC:
10

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
May 25, 2022
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
8.0
DANN
Benign
0.38
DEOGEN2
Benign
0.0029
T;T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.0054
N
LIST_S2
Benign
0.39
T;T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.011
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.42
.;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
1.1
N;N
REVEL
Benign
0.12
Sift
Benign
0.43
T;T
Sift4G
Benign
0.46
T;T
Polyphen
0.0
.;B
Vest4
0.11
MVP
0.13
MPC
0.058
ClinPred
0.0095
T
GERP RS
-0.51
Varity_R
0.030
gMVP
0.44

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: rs201907377; hg19: chr17-39633379; API