17-40751196-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_181534.4(KRT25):​c.800G>T​(p.Arg267Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267H) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KRT25
NM_181534.4 missense

Scores

5
11
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.90

Publications

15 publications found
Variant links:
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]
KRT25 Gene-Disease associations (from GenCC):
  • wooly hair, autosomal recessive 3
    Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • isolated familial wooly hair disorder
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KRT25NM_181534.4 linkc.800G>T p.Arg267Leu missense_variant Exon 4 of 8 ENST00000312150.5 NP_853512.1 Q7Z3Z0Q6ZPD6
KRT25XM_011524414.2 linkc.794G>T p.Arg265Leu missense_variant Exon 5 of 9 XP_011522716.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRT25ENST00000312150.5 linkc.800G>T p.Arg267Leu missense_variant Exon 4 of 8 1 NM_181534.4 ENSP00000310573.4 Q7Z3Z0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461824
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727214
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000180
AC:
2
AN:
1111948
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
53
Bravo
AF:
0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.82
T
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.91
D
MetaSVM
Uncertain
0.75
D
MutationAssessor
Benign
2.0
M
PhyloP100
2.9
PrimateAI
Uncertain
0.50
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.043
D
Polyphen
1.0
D
Vest4
0.73
MutPred
0.70
Loss of disorder (P = 0.044);
MVP
0.85
MPC
0.42
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.81
gMVP
0.95

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

Other links and lift over

dbSNP: rs72821893; hg19: chr17-38907448; API