chr21-44573796-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_198687.2(KRTAP10-4):​c.38G>A​(p.Arg13His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,613,848 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 0.00025 ( 0 hom., cov: 41)
Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

KRTAP10-4
NM_198687.2 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.179
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.031689048).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KRTAP10-4NM_198687.2 linkuse as main transcriptc.38G>A p.Arg13His missense_variant 1/1 ENST00000400374.4
TSPEARNM_144991.3 linkuse as main transcriptc.83-5791C>T intron_variant ENST00000323084.9
TSPEARNM_001272037.2 linkuse as main transcriptc.-122-5791C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KRTAP10-4ENST00000400374.4 linkuse as main transcriptc.38G>A p.Arg13His missense_variant 1/1 NM_198687.2 P1
TSPEARENST00000323084.9 linkuse as main transcriptc.83-5791C>T intron_variant 1 NM_144991.3 P1Q8WU66-1
TSPEARENST00000397916.1 linkuse as main transcriptn.21C>T non_coding_transcript_exon_variant 1/111
TSPEARENST00000642437.1 linkuse as main transcriptc.*28-5791C>T intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000250
AC:
38
AN:
152158
Hom.:
0
Cov.:
41
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000327
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000412
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000345
AC:
86
AN:
249450
Hom.:
0
AF XY:
0.000347
AC XY:
47
AN XY:
135328
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.000796
Gnomad EAS exome
AF:
0.0000555
Gnomad SAS exome
AF:
0.0000981
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000556
Gnomad OTH exome
AF:
0.000660
GnomAD4 exome
AF:
0.000398
AC:
581
AN:
1461572
Hom.:
0
Cov.:
195
AF XY:
0.000410
AC XY:
298
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.000612
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000479
Gnomad4 OTH exome
AF:
0.000315
GnomAD4 genome
AF:
0.000250
AC:
38
AN:
152276
Hom.:
0
Cov.:
41
AF XY:
0.000201
AC XY:
15
AN XY:
74454
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000412
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000595
Hom.:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000703
AC:
6
ExAC
AF:
0.000280
AC:
34
EpiCase
AF:
0.000545
EpiControl
AF:
0.00101

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 GeneticsAug 02, 2021The c.38G>A (p.R13H) alteration is located in exon 1 (coding exon 1) of the KRTAP10-4 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the arginine (R) at amino acid position 13 to be replaced by a histidine (H). 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
0.11
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
18
DANN
Uncertain
0.99
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.74
FATHMM_MKL
Benign
0.042
N
LIST_S2
Benign
0.22
T;.
M_CAP
Benign
0.0034
T
MetaRNN
Benign
0.032
T;T
MetaSVM
Benign
-0.87
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-2.4
.;N
REVEL
Benign
0.038
Sift
Benign
0.17
.;T
Sift4G
Benign
0.24
.;T
Vest4
0.16
MVP
0.072
MPC
0.58
ClinPred
0.026
T
GERP RS
2.1
gMVP
0.10

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: rs201059120; hg19: chr21-45993673; COSMIC: COSV59957889; API