21-44539397-A-G

Position:

chr21-44539397-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_198691.3(KRTAP10-1):c.754T>C(p.Cys252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,601,828 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00068 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 10 hom. )

Consequence

KRTAP10-1
NM_198691.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.312

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00451383).

BP6

Variant 21-44539397-A-G is Benign according to our data. Variant chr21-44539397-A-G is described in ClinVar as [Benign]. Clinvar id is 3025016.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000627 (909/1449638) while in subpopulation EAS AF= 0.017 (673/39526). AF 95% confidence interval is 0.016. There are 10 homozygotes in gnomad4_exome. There are 495 alleles in male gnomad4_exome subpopulation. Median coverage is 126. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KRTAP10-1	NM_198691.3 linkuse as main transcript	c.754T>C	p.Cys252Arg	missense_variant	1/1	ENST00000400375.1	NP_941964.2
TSPEAR	NM_144991.3 linkuse as main transcript	c.304-5474T>C		intron_variant		ENST00000323084.9	NP_659428.2
TSPEAR	NM_001272037.2 linkuse as main transcript	c.100-5474T>C		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.754T>C	p.Cys252Arg	missense_variant	1/1		NM_198691.3	ENSP00000383226	P1
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.304-5474T>C		intron_variant		1	NM_144991.3	ENSP00000321987	P1	Q8WU66-1
TSPEAR	ENST00000397916.1 linkuse as main transcript	n.259-5474T>C		intron_variant, non_coding_transcript_variant		1
TSPEAR	ENST00000642437.1 linkuse as main transcript	c.*249-5474T>C		intron_variant, NMD_transcript_variant				ENSP00000496535

Frequencies

GnomAD3 genomes

AF:

0.000684

AC:

104

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0152

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.00120

AC:

299

AN:

249896

Hom.:

AF XY:

0.00125

AC XY:

169

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0129

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000627

AC:

909

AN:

1449638

Hom.:

Cov.:

126

AF XY:

0.000686

AC XY:

495

AN XY:

721512

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0170

Gnomad4 SAS exome

AF:

0.000919

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000871

Gnomad4 OTH exome

AF:

0.000750

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152190

Hom.:

Cov.:

AF XY:

0.000793

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0153

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.000880

ExAC

AF:

0.00118

AC:

143

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

KRTAP10-1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.51

DEOGEN2

Benign

0.14

Eigen

Benign

-0.043

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

MutationTaster

Benign

0.99

D;D;N

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-6.7

REVEL

Benign

0.081

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.42

MVP

0.28

MPC

0.27

ClinPred

0.14

GERP RS

2.9

Varity_R

0.50

gMVP

0.048

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