NM_005172.2:c.414C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005172.2(ATOH1):c.414C>G(p.Asp138Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,613,986 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 45 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 73 hom. )

Consequence

ATOH1
NM_005172.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.22

Variant links:

Genes affected

ATOH1 (HGNC:797): (atonal bHLH transcription factor 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in neuron differentiation; positive regulation of neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including generation of neurons; inner ear morphogenesis; and positive regulation of inner ear auditory receptor cell differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ATOH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026541054).

BP6

Variant 4-93829340-C-G is Benign according to our data. Variant chr4-93829340-C-G is described in ClinVar as [Benign]. Clinvar id is 785105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0145 (2210/152296) while in subpopulation AFR AF= 0.0446 (1853/41564). AF 95% confidence interval is 0.0429. There are 45 homozygotes in gnomad4. There are 1022 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2210 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH1	NM_005172.2 link	c.414C>G	p.Asp138Glu	missense_variant	Exon 1 of 1	ENST00000306011.6	NP_005163.1	Q92858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATOH1	ENST00000306011.6 link	c.414C>G	p.Asp138Glu	missense_variant	Exon 1 of 1	6	NM_005172.2	ENSP00000302216.4		Q92858

Frequencies

GnomAD3 genomes

AF:

0.0145

AC:

2202

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0445

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00811

Gnomad ASJ

AF:

0.0334

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00597

AC:

1493

AN:

249902

Hom.:

AF XY:

0.00479

AC XY:

648

AN XY:

135310

show subpopulations

Gnomad AFR exome

AF:

0.0482

Gnomad AMR exome

AF:

0.00536

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00574

GnomAD4 exome

AF:

0.00283

AC:

4143

AN:

1461690

Hom.:

Cov.:

AF XY:

0.00270

AC XY:

1962

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0490

Gnomad4 AMR exome

AF:

0.00579

Gnomad4 ASJ exome

AF:

0.0331

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000776

Gnomad4 OTH exome

AF:

0.00663

GnomAD4 genome

AF:

0.0145

AC:

2210

AN:

152296

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1022

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0446

Gnomad4 AMR

AF:

0.00810

Gnomad4 ASJ

AF:

0.0334

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00555

Hom.:

Bravo

AF:

0.0169

ESP6500AA

AF:

0.0436

AC:

192

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00614

AC:

745

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATOH1-related disorder

Benign:1

Jun 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.39

CADD

Benign

4.8

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.61

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.29

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.69

REVEL

Benign

0.24

Sift

Benign

0.035

Sift4G

Benign

0.14

Polyphen

0.0010

Vest4

0.052

MutPred

0.21

Gain of glycosylation at S143 (P = 0.0219);

MVP

0.71

MPC

0.57

ClinPred

0.0036

GERP RS

-0.71

Varity_R

0.083

gMVP

0.27

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