dbSNP rs76743925: KRTAP10-10:p.Asp83Ala (chr21-44637665-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_181688.3(KRTAP10-10):c.248A>C(p.Asp83Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,574,330 control chromosomes in the GnomAD database, including 105 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 Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 38 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 67 hom. )

Consequence

KRTAP10-10
NM_181688.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0100

Publications

4 publications found

Variant links:

Genes affected

KRTAP10-10 (HGNC:22972): (keratin associated protein 10-10) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP10-10 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=0.0061335564).

BP6

Variant 21-44637665-A-C is Benign according to our data. Variant chr21-44637665-A-C is described in ClinVar as Benign. ClinVar VariationId is 377201.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 = 0.0148 (2199/148694) while in subpopulation AFR AF = 0.0506 (2017/39846). AF 95% confidence interval is 0.0488. There are 38 homozygotes in GnomAd4. There are 1005 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181688.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRTAP10-10	NM_181688.3	MANE Select	c.248A>C	p.Asp83Ala	missense	Exon 1 of 1	NP_859016.1
TSPEAR	NM_144991.3	MANE Select	c.83-69660T>G		intron	N/A	NP_659428.2
TSPEAR	NM_001272037.2		c.-123+52880T>G		intron	N/A	NP_001258966.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KRTAP10-10	ENST00000380095.2	TSL:6 MANE Select	c.248A>C	p.Asp83Ala	missense	Exon 1 of 1	ENSP00000369438.1
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-69660T>G		intron	N/A	ENSP00000321987.4
TSPEAR	ENST00000642437.1		n.*27+52880T>G		intron	N/A	ENSP00000496535.1

Frequencies

GnomAD3 genomes

AF:

0.0147

AC:

2191

AN:

148578

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0505

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00546

Gnomad ASJ

AF:

0.00639

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.000215

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0200

Gnomad NFE

AF:

0.000729

Gnomad OTH

AF:

0.0103

GnomAD2 exomes

AF:

0.00397

AC:

996

AN:

250568

AF XY:

0.00295

show subpopulations

Gnomad AFR exome

AF:

0.0489

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00164

AC:

2340

AN:

1425636

Hom.:

Cov.:

135

AF XY:

0.00150

AC XY:

1063

AN XY:

708420

show subpopulations

African (AFR)

AF:

0.0470

AC:

1461

AN:

31104

American (AMR)

AF:

0.00352

AC:

139

AN:

39482

Ashkenazi Jewish (ASJ)

AF:

0.00425

AC:

106

AN:

24970

East Asian (EAS)

AF:

0.0000520

AC:

AN:

38440

South Asian (SAS)

AF:

0.000230

AC:

AN:

82546

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52342

Middle Eastern (MID)

AF:

0.0101

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.000273

AC:

298

AN:

1092534

Other (OTH)

AF:

0.00439

AC:

257

AN:

58582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

140

279

419

558

698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.0148

AC:

2199

AN:

148694

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1005

AN XY:

72534

show subpopulations

African (AFR)

AF:

0.0506

AC:

2017

AN:

39846

American (AMR)

AF:

0.00545

AC:

AN:

15048

Ashkenazi Jewish (ASJ)

AF:

0.00639

AC:

AN:

3444

East Asian (EAS)

AF:

0.000401

AC:

AN:

4982

South Asian (SAS)

AF:

0.000215

AC:

AN:

4644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10254

Middle Eastern (MID)

AF:

0.0216

AC:

AN:

278

European-Non Finnish (NFE)

AF:

0.000714

AC:

AN:

67246

Other (OTH)

AF:

0.0102

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.00945

Hom.:

ESP6500AA

AF:

0.0477

AC:

210

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00500

AC:

607

ClinVar

Significance: 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 29, 2016

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.019

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.0028

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.00015

LIST_S2

Benign

0.0091

MetaRNN

Benign

0.0061

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-2.9

PhyloP100

0.010

PrimateAI

Benign

0.20

PROVEAN

Benign

4.2

REVEL

Benign

0.047

Sift

Benign

0.94

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.037

MVP

0.12

MPC

0.056

ClinPred

0.0073

GERP RS

0.25

PromoterAI

-0.033

Neutral

(source)

Varity_R

0.044

gMVP

0.042

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over