chr21-44592378-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_198688.3(KRTAP10-6):c.107A>C(p.Asp36Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,521,062 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 7 hom., cov: 24)

Exomes 𝑓: 0.0014 ( 92 hom. )

Consequence

KRTAP10-6
NM_198688.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.07

Publications

2 publications found

Variant links:

Genes affected

KRTAP10-6 (HGNC:20523): (keratin associated protein 10-6) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP10-6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063505173).

BP6

Variant 21-44592378-T-G is Benign according to our data. Variant chr21-44592378-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 235482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRTAP10-6	NM_198688.3 link	c.107A>C	p.Asp36Ala	missense_variant	Exon 1 of 1	ENST00000400368.1	NP_941961.3	P60371
TSPEAR	NM_144991.3 link	c.83-24373A>C		intron_variant	Intron 1 of 11	ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 link	c.-122-24373A>C		intron_variant	Intron 2 of 12		NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRTAP10-6	ENST00000400368.1 link	c.107A>C	p.Asp36Ala	missense_variant	Exon 1 of 1	6	NM_198688.3	ENSP00000383219.1	P60371
TSPEAR	ENST00000323084.9 link	c.83-24373A>C		intron_variant	Intron 1 of 11	1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 link	n.*28-24373A>C		intron_variant	Intron 2 of 12			ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.00580

AC:

672

AN:

115942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0159

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00326

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00102

Gnomad FIN

AF:

0.000637

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00477

GnomAD2 exomes

AF:

0.00946

AC:

2271

AN:

240130

AF XY:

0.00932

show subpopulations

Gnomad AFR exome

AF:

0.0246

Gnomad AMR exome

AF:

0.00399

Gnomad ASJ exome

AF:

0.00161

Gnomad EAS exome

AF:

0.00280

Gnomad FIN exome

AF:

0.00542

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00874

GnomAD4 exome

AF:

0.00141

AC:

1975

AN:

1405010

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

943

AN XY:

696404

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0197

AC:

635

AN:

32256

American (AMR)

AF:

0.00144

AC:

AN:

43102

Ashkenazi Jewish (ASJ)

AF:

0.000450

AC:

AN:

24430

East Asian (EAS)

AF:

0.000558

AC:

AN:

39452

South Asian (SAS)

AF:

0.00277

AC:

226

AN:

81606

European-Finnish (FIN)

AF:

0.000586

AC:

AN:

51202

Middle Eastern (MID)

AF:

0.00262

AC:

AN:

4584

European-Non Finnish (NFE)

AF:

0.000792

AC:

848

AN:

1070324

Other (OTH)

AF:

0.00222

AC:

129

AN:

58054

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

188

281

375

469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<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:

0.00580

AC:

673

AN:

116052

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

317

AN XY:

55206

show subpopulations

African (AFR)

AF:

0.0158

AC:

545

AN:

34424

American (AMR)

AF:

0.00326

AC:

AN:

11364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2878

East Asian (EAS)

AF:

0.00156

AC:

AN:

4498

South Asian (SAS)

AF:

0.00102

AC:

AN:

2946

European-Finnish (FIN)

AF:

0.000637

AC:

AN:

6280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

51250

Other (OTH)

AF:

0.00469

AC:

AN:

1492

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

100

125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0103

Hom.:

ESP6500AA

AF:

0.0255

AC:

103

ESP6500EA

AF:

0.0141

AC:

117

ExAC

AF:

0.0115

AC:

1390

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

- -

May 12, 2016

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

0.23

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

0.018

Eigen_PC

Benign

-0.043

FATHMM_MKL

Benign

0.25

MetaRNN

Benign

0.0064

MetaSVM

Benign

-1.1

PhyloP100

2.1

PROVEAN

Pathogenic

-6.6

REVEL

Benign

0.11

Sift

Uncertain

0.026

Sift4G

Benign

0.11

Vest4

0.15

MPC

0.60

ClinPred

0.035

GERP RS

2.2

PromoterAI

0.022

Neutral

(source)

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(source)

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

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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