17-41026722-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031957.2(KRTAP1-5):​c.434A>T​(p.Gln145Leu) 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 1,461,538 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

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

Consequence

KRTAP1-5
NM_031957.2 missense

Scores

4
7
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.27
Variant links:
Genes affected
KRTAP1-5 (HGNC:16777): (keratin associated protein 1-5) This protein is a member of the keratin-associated protein (KAP) family. The KAP proteins form a matrix of keratin intermediate filaments which contribute to the structure of hair fibers. KAP family members appear to have unique, family-specific amino- and carboxyl-terminal regions and are subdivided into three multi-gene families according to amino acid composition: the high sulfur, the ultrahigh sulfur, and the high tyrosine/glycine KAPs. This protein is a member of the high sulfur KAP family and the gene is localized to a cluster of KAPs at 17q12-q21. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KRTAP1-5NM_031957.2 linkuse as main transcriptc.434A>T p.Gln145Leu missense_variant 1/1 ENST00000361883.6 NP_114163.1 Q9BYS1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KRTAP1-5ENST00000361883.6 linkuse as main transcriptc.434A>T p.Gln145Leu missense_variant 1/16 NM_031957.2 ENSP00000355302.5 Q9BYS1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461538
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727088
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000111
Hom.:
0

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 26, 2024The c.434A>T (p.Q145L) alteration is located in exon 1 (coding exon 1) of the KRTAP1-5 gene. This alteration results from a A to T substitution at nucleotide position 434, causing the glutamine (Q) at amino acid position 145 to be replaced by a leucine (L). 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
0.28
BayesDel_addAF
Uncertain
0.062
T
BayesDel_noAF
Benign
-0.15
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.028
T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.81
D
M_CAP
Benign
0.013
T
MetaRNN
Uncertain
0.67
D
MetaSVM
Benign
-0.34
T
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Benign
0.41
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.34
Sift
Uncertain
0.027
D
Sift4G
Uncertain
0.034
D
Polyphen
1.0
D
Vest4
0.58
MutPred
0.71
Gain of catalytic residue at Q145 (P = 0.095);
MVP
0.51
MPC
0.39
ClinPred
0.99
D
GERP RS
5.5
Varity_R
0.44
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1597944208; hg19: chr17-39182974; API