Genetic Variant NM_198688.3:c.331G>C (chr21-44592154-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198688.3(KRTAP10-6):c.331G>C(p.Val111Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,426,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V111M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 20)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

KRTAP10-6
NM_198688.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.337

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.083043665).

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>C	p.Val111Leu	missense	Exon 1 of 1	NP_941961.3	P60371
TSPEAR	NM_144991.3	MANE Select	c.83-24149G>C		intron	N/A	NP_659428.2
TSPEAR	NM_001272037.2		c.-122-24149G>C		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>C	p.Val111Leu	missense	Exon 1 of 1	ENSP00000383219.1	P60371
TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.83-24149G>C		intron	N/A	ENSP00000321987.4	Q8WU66-1
TSPEAR	ENST00000943283.1		c.83-24149G>C		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1426746

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

710032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31204

American (AMR)

AF:

0.00

AC:

AN:

43608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25750

East Asian (EAS)

AF:

0.00

AC:

AN:

38934

South Asian (SAS)

AF:

0.00

AC:

AN:

84568

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000552

AC:

AN:

1086298

Other (OTH)

AF:

0.00

AC:

AN:

58796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.70

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.10

M_CAP

Benign

0.0029

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.95

PhyloP100

-0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.014

Sift

Benign

0.11

Sift4G

Benign

0.32

Vest4

0.058

MutPred

0.40

Loss of sheet (P = 0.0315)

MVP

0.014

MPC

0.47

ClinPred

0.11

GERP RS

-0.96

PromoterAI

-0.0030

Neutral

(source)

gMVP

0.057

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over