rs11910525

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_198691.3(KRTAP10-1):c.22G>A(p.Val8Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,608 control chromosomes in the GnomAD database, including 37 homozygotes. 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 0.0063 ( 11 hom., cov: 33)

Exomes 𝑓: 0.0021 ( 26 hom. )

Consequence

KRTAP10-1
NM_198691.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.867

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive nonsyndromic hearing loss 98
Inheritance: AR Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

TSPEAR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004553348).

BP6

Variant 21-44540129-C-T is Benign according to our data. Variant chr21-44540129-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 376948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00627 (955/152198) while in subpopulation AFR AF = 0.0186 (771/41512). AF 95% confidence interval is 0.0175. There are 11 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-1	NM_198691.3 link	c.22G>A	p.Val8Ile	missense_variant	Exon 1 of 1	ENST00000400375.1	NP_941964.2	P60331
TSPEAR	NM_144991.3 link	c.304-6206G>A		intron_variant	Intron 2 of 11	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.100-6206G>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.22G>A	p.Val8Ile	missense_variant	Exon 1 of 1	6	NM_198691.3	ENSP00000383226.1	P60331
TSPEAR	ENST00000323084.9 link	c.304-6206G>A		intron_variant	Intron 2 of 11	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000397916.1 link	n.259-6206G>A		intron_variant	Intron 2 of 10	1
TSPEAR	ENST00000642437.1 link	n.*249-6206G>A		intron_variant	Intron 3 of 12			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

949

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0185

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00830

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00337

AC:

845

AN:

250830

AF XY:

0.00353

show subpopulations

Gnomad AFR exome

AF:

0.0182

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00409

Gnomad EAS exome

AF:

0.000982

Gnomad FIN exome

AF:

0.000742

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00207

AC:

3022

AN:

1461410

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1609

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.0219

AC:

732

AN:

33460

American (AMR)

AF:

0.00141

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00410

AC:

107

AN:

26092

East Asian (EAS)

AF:

0.000856

AC:

AN:

39698

South Asian (SAS)

AF:

0.00759

AC:

654

AN:

86190

European-Finnish (FIN)

AF:

0.000506

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00923

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00105

AC:

1166

AN:

1111884

Other (OTH)

AF:

0.00310

AC:

187

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

238

476

715

953

1191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00627

AC:

955

AN:

152198

Hom.:

Cov.:

AF XY:

0.00601

AC XY:

447

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0186

AC:

771

AN:

41512

American (AMR)

AF:

0.00183

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5172

South Asian (SAS)

AF:

0.00831

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

67992

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00378

Hom.:

Bravo

AF:

0.00710

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00389

AC:

472

EpiCase

AF:

0.00136

EpiControl

AF:

0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.51

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

PhyloP100

-0.87

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.65

REVEL

Benign

0.030

Sift

Benign

0.39

Sift4G

Benign

0.34

Polyphen

0.027

Vest4

0.099

MVP

0.17

MPC

0.15

ClinPred

0.00057

GERP RS

0.59

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.023

gMVP

0.026

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over