21-44539382-A-T

Variant names:

Variant summary

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

The NM_198691.3(KRTAP10-1):c.769T>A(p.Ser257Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

KRTAP10-1
NM_198691.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.632

Variant links:

Genes affected

KRTAP10-1 (HGNC:22966): (keratin associated protein 10-1) This gene encodes 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 gene encodes a member of the high sulfur KAP family. It is localized to a cluster of intronless KAPs at 21q22.3 which are located within the introns of the C21orf29 gene. [provided by RefSeq, Jul 2008]

KRTAP10-1 links:

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]

TSPEAR links:

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=0.12438202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-1	NM_198691.3 link	c.769T>A	p.Ser257Thr	missense_variant	Exon 1 of 1	ENST00000400375.1	NP_941964.2	P60331
TSPEAR	NM_144991.3 link	c.304-5459T>A		intron_variant	Intron 2 of 11	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.100-5459T>A		intron_variant	Intron 3 of 12		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRTAP10-1	ENST00000400375.1 link	c.769T>A	p.Ser257Thr	missense_variant	Exon 1 of 1	6	NM_198691.3	ENSP00000383226.1	P60331
TSPEAR	ENST00000323084.9 link	c.304-5459T>A		intron_variant	Intron 2 of 11	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 link	n.259-5459T>A		intron_variant	Intron 2 of 10	1
TSPEAR	ENST00000642437.1 link	n.*249-5459T>A		intron_variant	Intron 3 of 12			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249278

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135060

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1460474

Hom.:

Cov.:

126

AF XY:

0.00000688

AC XY:

AN XY:

726544

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.769T>A (p.S257T) alteration is located in exon 1 (coding exon 1) of the KRTAP10-1 gene. This alteration results from a T to A substitution at nucleotide position 769, causing the serine (S) at amino acid position 257 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.028

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.31

M_CAP

Benign

0.0039

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.4

REVEL

Benign

0.061

Sift

Benign

0.28

Sift4G

Benign

0.38

Polyphen

0.86

Vest4

0.11

MutPred

0.39

Gain of relative solvent accessibility (P = 0.0479);

MVP

0.40

MPC

0.14

ClinPred

0.088

GERP RS

1.7

Varity_R

0.049

gMVP

0.025

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over