21-44558169-T-A

Position:

chr21-44558169-T-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_198696.3(KRTAP10-3):c.547A>T(p.Thr183Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,604,928 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 Likely benign (★).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

KRTAP10-3
NM_198696.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0740

Variant links:

Genes affected

KRTAP10-3 (HGNC:22968): (keratin associated protein 10-3) 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]

KRTAP10-3 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:

TSPEAR (HGNC:):

TSPEAR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0099217).

BP6

Variant 21-44558169-T-A is Benign according to our data. Variant chr21-44558169-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 2570292.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-3	NM_198696.3 linkuse as main transcript	c.547A>T	p.Thr183Ser	missense_variant	1/1	ENST00000391620.2	NP_941969.2	P60369
TSPEAR	NM_144991.3 linkuse as main transcript	c.303+9616A>T		intron_variant		ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.99+9616A>T		intron_variant			NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRTAP10-3	ENST00000391620.2 linkuse as main transcript	c.547A>T	p.Thr183Ser	missense_variant	1/1	6	NM_198696.3	ENSP00000375478.1	P60369
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.303+9616A>T		intron_variant		1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.258+9616A>T		intron_variant		1
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.*248+9616A>T		intron_variant				ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.000394

AC:

AN:

147252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000582

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000335

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000409

Gnomad SAS

AF:

0.00109

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000346

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000331

AC:

AN:

248086

Hom.:

AF XY:

0.000401

AC XY:

AN XY:

134566

show subpopulations

Gnomad AFR exome

AF:

0.000386

Gnomad AMR exome

AF:

0.000523

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.000390

Gnomad SAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000285

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000307

AC:

448

AN:

1457556

Hom.:

Cov.:

AF XY:

0.000342

AC XY:

248

AN XY:

725042

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.000523

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.000406

Gnomad4 SAS exome

AF:

0.000444

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000296

Gnomad4 OTH exome

AF:

0.000416

GnomAD4 genome

AF:

0.000394

AC:

AN:

147372

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

71982

show subpopulations

Gnomad4 AFR

AF:

0.000580

Gnomad4 AMR

AF:

0.000334

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000410

Gnomad4 SAS

AF:

0.00109

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000346

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000202

Hom.:

Bravo

AF:

0.000419

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.052

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.15

DANN

Benign

0.45

DEOGEN2

Benign

0.00076

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.038

M_CAP

Benign

0.00085

MetaRNN

Benign

0.0099

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.6

PrimateAI

Benign

0.22

PROVEAN

Benign

2.1

REVEL

Benign

0.057

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.020

MutPred

0.36

Loss of glycosylation at S182 (P = 0.0634);

MVP

0.076

MPC

0.022

ClinPred

0.0092

GERP RS

0.096

Varity_R

0.032

gMVP

0.023

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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