21-44592154-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_198688.3(KRTAP10-6):c.331G>A(p.Val111Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000282 in 1,563,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 20)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

KRTAP10-6
NM_198688.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.337

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive nonsyndromic hearing loss 98
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010167271).

BP6

Variant 21-44592154-C-T is Benign according to our data. Variant chr21-44592154-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2652768.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198688.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP10-6	NM_198688.3	MANE Select	c.331G>A	p.Val111Met	missense	Exon 1 of 1	NP_941961.3	P60371
TSPEAR	NM_144991.3	MANE Select	c.83-24149G>A		intron	N/A	NP_659428.2
TSPEAR	NM_001272037.2		c.-122-24149G>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP10-6	ENST00000400368.1	TSL:6 MANE Select	c.331G>A	p.Val111Met	missense	Exon 1 of 1	ENSP00000383219.1	P60371
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-24149G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000943283.1		c.83-24149G>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes

AF:

0.000983

AC:

135

AN:

137348

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000778

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000158

Gnomad OTH

AF:

0.00212

GnomAD2 exomes

AF:

0.000460

AC:

110

AN:

238972

AF XY:

0.000400

show subpopulations

Gnomad AFR exome

AF:

0.00440

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000575

Gnomad FIN exome

AF:

0.0000480

Gnomad NFE exome

AF:

0.000316

Gnomad OTH exome

AF:

0.000339

GnomAD4 exome

AF:

0.000215

AC:

306

AN:

1426062

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

153

AN XY:

709708

show subpopulations

African (AFR)

AF:

0.00353

AC:

110

AN:

31140

American (AMR)

AF:

0.000321

AC:

AN:

43598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25748

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38934

South Asian (SAS)

AF:

0.0000710

AC:

AN:

84552

European-Finnish (FIN)

AF:

0.0000192

AC:

AN:

52174

Middle Eastern (MID)

AF:

0.000185

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.000132

AC:

143

AN:

1085748

Other (OTH)

AF:

0.000511

AC:

AN:

58758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000982

AC:

135

AN:

137462

Hom.:

Cov.:

AF XY:

0.000871

AC XY:

AN XY:

66628

show subpopulations

African (AFR)

AF:

0.00311

AC:

110

AN:

35404

American (AMR)

AF:

0.000777

AC:

AN:

14160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3300

East Asian (EAS)

AF:

0.00

AC:

AN:

4828

South Asian (SAS)

AF:

0.00

AC:

AN:

4232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9120

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.000158

AC:

AN:

63452

Other (OTH)

AF:

0.00210

AC:

AN:

1904

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000590

Hom.:

ESP6500AA

AF:

0.00323

AC:

ESP6500EA

AF:

0.000475

AC:

ExAC

AF:

0.000460

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.7

(source)

DANN

Benign

0.84

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.014

M_CAP

Benign

0.0042

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.96

PhyloP100

-0.34

PROVEAN

Benign

-1.6

REVEL

Benign

0.017

Sift

Benign

0.075

Sift4G

Benign

0.11

Vest4

0.073

MVP

0.014

MPC

0.48

ClinPred

0.0092

GERP RS

-0.96

PromoterAI

-0.077

Neutral

(source)

gMVP

0.060

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over