Genetic Variant ATOH8:p.Ala113Val (chr2-85754527-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_032827.7(ATOH8):c.338C>T(p.Ala113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,431,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.728

Variant links:

Genes affected

ATOH8 (HGNC:24126): (atonal bHLH transcription factor 8) Enables DNA-binding transcription factor activity and E-box binding activity. Involved in several processes, including SMAD protein signal transduction; positive regulation of endothelial cell differentiation; and regulation of gene expression. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ATOH8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27274263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH8	NM_032827.7 link	c.338C>T	p.Ala113Val	missense_variant	Exon 1 of 3	ENST00000306279.4	NP_116216.2	Q96SQ7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ATOH8	ENST00000306279.4 link	c.338C>T	p.Ala113Val	missense_variant	Exon 1 of 3	1	NM_032827.7	ENSP00000304676.3	Q96SQ7-1
ATOH8	ENST00000469442.5 link	n.519+2665C>T		intron_variant	Intron 1 of 2	2
ATOH8	ENST00000463422.5 link	n.-120C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000902

AC:

AN:

33256

Hom.:

AF XY:

0.0000532

AC XY:

AN XY:

18804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000455

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000469

AC:

AN:

1278780

Hom.:

Cov.:

AF XY:

0.00000320

AC XY:

AN XY:

625080

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000329

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.65e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.338C>T (p.A113V) alteration is located in exon 1 (coding exon 1) of the ATOH8 gene. This alteration results from a C to T substitution at nucleotide position 338, causing the alanine (A) at amino acid position 113 to be replaced by a valine (V). 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

0.10

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.27

MetaSVM

Uncertain

-0.080

MutationAssessor

Benign

0.81

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.39

REVEL

Benign

0.28

Sift

Benign

0.061

Sift4G

Benign

0.39

Polyphen

0.18

Vest4

0.30

MutPred

0.31

Loss of helix (P = 0.0093);

MVP

0.39

MPC

0.62

ClinPred

0.10

GERP RS

2.7

Varity_R

0.078

gMVP

0.17

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