21-44539607-C-A

Position:

chr21-44539607-C-A

Variant summary

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

The NM_198691.3(KRTAP10-1):c.544G>T(p.Ala182Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,612,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

KRTAP10-1
NM_198691.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.13

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 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=0.010534793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRTAP10-1	NM_198691.3 linkuse as main transcript	c.544G>T	p.Ala182Ser	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3 linkuse as main transcript	c.304-5684G>T		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.100-5684G>T		intron_variant			NP_001258966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRTAP10-1	ENST00000400375.1 linkuse as main transcript	c.544G>T	p.Ala182Ser	missense_variant	1/1		NM_198691.3	ENSP00000383226	P1
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.304-5684G>T		intron_variant		1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.259-5684G>T		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*249-5684G>T		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.000404

AC:

AN:

151156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000113

AC:

AN:

248008

Hom.:

AF XY:

0.0000894

AC XY:

AN XY:

134252

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000664

AC:

AN:

1461526

Hom.:

Cov.:

175

AF XY:

0.0000674

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000387

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000397

AC:

AN:

151266

Hom.:

Cov.:

AF XY:

0.000433

AC XY:

AN XY:

73906

show subpopulations

Gnomad4 AFR

AF:

0.00136

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000403

Hom.:

Bravo

AF:

0.000672

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.544G>T (p.A182S) alteration is located in exon 1 (coding exon 1) of the KRTAP10-1 gene. This alteration results from a G to T substitution at nucleotide position 544, causing the alanine (A) at amino acid position 182 to be replaced by a serine (S). 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

0.059

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.74

DANN

Benign

0.81

DEOGEN2

Benign

0.0015

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.035

M_CAP

Benign

0.0015

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.030

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.88

REVEL

Benign

0.014

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.011

Vest4

0.054

MVP

0.16

MPC

0.14

ClinPred

0.0028

GERP RS

-4.5

Varity_R

0.044

gMVP

0.020

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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