chr21-44573804-C-T

Variant summary

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

The NM_198687.2(KRTAP10-4):​c.46C>T​(p.Leu16Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 41)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

KRTAP10-4
NM_198687.2 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.08
Variant links:
Genes affected
KRTAP10-4 (HGNC:20521): (keratin associated protein 10-4) This is an intronless gene located in a cluster of related genes on the q arm of chromosome 21. The proteins encoded by these genes form disulfide bonds with cysteine residues in hair keratins, thereby contributing to the structure and stability of hair fibers. [provided by RefSeq, Apr 2014]
TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

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=0.08382833).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRTAP10-4NM_198687.2 linkuse as main transcriptc.46C>T p.Leu16Phe missense_variant 1/1 ENST00000400374.4
TSPEARNM_144991.3 linkuse as main transcriptc.83-5799G>A intron_variant ENST00000323084.9
TSPEARNM_001272037.2 linkuse as main transcriptc.-122-5799G>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRTAP10-4ENST00000400374.4 linkuse as main transcriptc.46C>T p.Leu16Phe missense_variant 1/1 NM_198687.2 P1
TSPEARENST00000323084.9 linkuse as main transcriptc.83-5799G>A intron_variant 1 NM_144991.3 P1Q8WU66-1
TSPEARENST00000397916.1 linkuse as main transcriptn.13G>A non_coding_transcript_exon_variant 1/111
TSPEARENST00000642437.1 linkuse as main transcriptc.*28-5799G>A intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000105
AC:
16
AN:
152244
Hom.:
0
Cov.:
41
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000922
AC:
23
AN:
249436
Hom.:
0
AF XY:
0.0000739
AC XY:
10
AN XY:
135320
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000112
AC:
164
AN:
1461844
Hom.:
0
Cov.:
195
AF XY:
0.0000935
AC XY:
68
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000144
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000105
AC:
16
AN:
152244
Hom.:
0
Cov.:
41
AF XY:
0.0000807
AC XY:
6
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000818
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000234
AC:
2
ExAC
AF:
0.0000990
AC:
12
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 GeneticsJul 19, 2023The c.46C>T (p.L16F) alteration is located in exon 1 (coding exon 1) of the KRTAP10-4 gene. This alteration results from a C to T substitution at nucleotide position 46, causing the leucine (L) at amino acid position 16 to be replaced by a phenylalanine (F). 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
0.12
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
14
DANN
Uncertain
0.99
Eigen
Benign
-0.67
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.39
N
LIST_S2
Benign
0.35
T;.
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.084
T;T
MetaSVM
Benign
-0.94
T
MutationTaster
Benign
1.0
D;D;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.7
.;N
REVEL
Benign
0.085
Sift
Uncertain
0.020
.;D
Sift4G
Uncertain
0.055
.;T
Vest4
0.066
MVP
0.072
MPC
0.58
ClinPred
0.084
T
GERP RS
-2.0
gMVP
0.080

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: rs374080725; hg19: chr21-45993681; API