NM_198688.3:c.107A>C

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

1
1
12

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]
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

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
KRTAP10-6NM_198688.3 linkc.107A>C p.Asp36Ala missense_variant Exon 1 of 1 ENST00000400368.1 NP_941961.3 P60371
TSPEARNM_144991.3 linkc.83-24373A>C intron_variant Intron 1 of 11 ENST00000323084.9 NP_659428.2 Q8WU66-1
TSPEARNM_001272037.2 linkc.-122-24373A>C intron_variant Intron 2 of 12 NP_001258966.1 Q8WU66

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KRTAP10-6ENST00000400368.1 linkc.107A>C p.Asp36Ala missense_variant Exon 1 of 1 6 NM_198688.3 ENSP00000383219.1 P60371
TSPEARENST00000323084.9 linkc.83-24373A>C intron_variant Intron 1 of 11 1 NM_144991.3 ENSP00000321987.4 Q8WU66-1
TSPEARENST00000642437.1 linkn.*28-24373A>C intron_variant Intron 2 of 12 ENSP00000496535.1 A0A2R8YFK6

Frequencies

GnomAD3 genomes
AF:
0.00580
AC:
672
AN:
115942
Hom.:
7
Cov.:
24
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.:
92
Cov.:
33
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:
62
AN:
43102
Ashkenazi Jewish (ASJ)
AF:
0.000450
AC:
11
AN:
24430
East Asian (EAS)
AF:
0.000558
AC:
22
AN:
39452
South Asian (SAS)
AF:
0.00277
AC:
226
AN:
81606
European-Finnish (FIN)
AF:
0.000586
AC:
30
AN:
51202
Middle Eastern (MID)
AF:
0.00262
AC:
12
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
0
94
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
0
44
88
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.:
7
Cov.:
24
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:
37
AN:
11364
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2878
East Asian (EAS)
AF:
0.00156
AC:
7
AN:
4498
South Asian (SAS)
AF:
0.00102
AC:
3
AN:
2946
European-Finnish (FIN)
AF:
0.000637
AC:
4
AN:
6280
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
240
European-Non Finnish (NFE)
AF:
0.00137
AC:
70
AN:
51250
Other (OTH)
AF:
0.00469
AC:
7
AN:
1492
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.413
Heterozygous variant carriers
0
25
50
75
100
125
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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.:
2
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
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
20
DANN
Benign
0.93
Eigen
Benign
0.018
Eigen_PC
Benign
-0.043
FATHMM_MKL
Benign
0.25
N
MetaRNN
Benign
0.0064
T
MetaSVM
Benign
-1.1
T
PhyloP100
2.1
PROVEAN
Pathogenic
-6.6
D
REVEL
Benign
0.11
Sift
Uncertain
0.026
D
Sift4G
Benign
0.11
T
Vest4
0.15
MPC
0.60
ClinPred
0.035
T
GERP RS
2.2
PromoterAI
0.022
Neutral
gMVP
0.18
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs201362069; hg19: chr21-46012259; COSMIC: COSV59961818; API