Variant chr21-44697241-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198699.1(KRTAP10-12):c.40G>A(p.Val14Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,020 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 2 hom. )

Consequence

KRTAP10-12
NM_198699.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.212

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034659296).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRTAP10-12	NM_198699.1 linkuse as main transcript	c.40G>A	p.Val14Ile	missense_variant	1/1	ENST00000400365.3	NP_941972.1	P60413
TSPEAR	NM_144991.3 linkuse as main transcript	c.82+14192C>T		intron_variant		ENST00000323084.9	NP_659428.2	Q8WU66-1
TSPEAR	NM_001272037.2 linkuse as main transcript	c.-184-6635C>T		intron_variant			NP_001258966.1	Q8WU66

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KRTAP10-12	ENST00000400365.3 linkuse as main transcript	c.40G>A	p.Val14Ile	missense_variant	1/1	6	NM_198699.1	ENSP00000383216.3	P60413
TSPEAR	ENST00000323084.9 linkuse as main transcript	c.82+14192C>T		intron_variant		1	NM_144991.3	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000642437.1 linkuse as main transcript	n.83-6635C>T		intron_variant				ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249472

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000334

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

224

AN:

1461784

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00531

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.00000756

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.40G>A (p.V14I) alteration is located in exon 1 (coding exon 1) of the KRTAP10-12 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.8

DANN

Benign

0.62

DEOGEN2

Benign

0.0019

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.68

M_CAP

Benign

0.013

MetaRNN

Benign

0.035

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.47

REVEL

Benign

0.046

Sift

Benign

0.42

Sift4G

Benign

0.33

Polyphen

0.66

Vest4

0.079

MutPred

0.39

Gain of relative solvent accessibility (P = 0.1259);

MVP

0.014

MPC

0.40

ClinPred

0.019

GERP RS

0.41

Varity_R

0.019

gMVP

0.026

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over