NM_198699.1:c.248C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_198699.1(KRTAP10-12):c.248C>T(p.Ser83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,614,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S83W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

KRTAP10-12
NM_198699.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.671

Publications

1 publications found

Variant links:

Genes affected

KRTAP10-12 (HGNC:20533): (keratin associated protein 10-12) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP10-12 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018850505).

BP6

Variant 21-44697449-C-T is Benign according to our data. Variant chr21-44697449-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1301812.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198699.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP10-12	NM_198699.1	MANE Select	c.248C>T	p.Ser83Leu	missense	Exon 1 of 1	NP_941972.1	P60413
TSPEAR	NM_144991.3	MANE Select	c.82+13984G>A		intron	N/A	NP_659428.2
TSPEAR	NM_001272037.2		c.-184-6843G>A		intron	N/A	NP_001258966.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KRTAP10-12	ENST00000400365.3	TSL:6 MANE Select	c.248C>T	p.Ser83Leu	missense	Exon 1 of 1	ENSP00000383216.3	P60413
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+13984G>A		intron	N/A	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000943283.1		c.82+13984G>A		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000352

AC:

AN:

249970

AF XY:

0.000398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.000823

GnomAD4 exome

AF:

0.000254

AC:

372

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

189

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33470

American (AMR)

AF:

0.000738

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00714

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000173

AC:

192

AN:

1111988

Other (OTH)

AF:

0.000563

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

114

152

190

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:

0.000263

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.000588

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000536

Hom.:

Bravo

AF:

0.000287

ExAC

AF:

0.000354

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 98 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.034

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.16

M_CAP

Benign

0.0038

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.4

PhyloP100

0.67

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.029

Sift

Benign

0.084

Sift4G

Benign

0.095

Polyphen

0.0020

Vest4

0.27

MVP

0.030

MPC

0.24

ClinPred

0.035

GERP RS

0.16

PromoterAI

0.043

Neutral

(source)

Varity_R

0.078

gMVP

0.037

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over