Genetic Variant NM_032827.7:c.154C>T (chr2-85754343-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_032827.7(ATOH8):c.154C>T(p.Pro52Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 in 1,607,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.418

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09683418).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032827.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATOH8	NM_032827.7	MANE Select	c.154C>T	p.Pro52Ser	missense	Exon 1 of 3	NP_116216.2	Q96SQ7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATOH8	ENST00000306279.4	TSL:1 MANE Select	c.154C>T	p.Pro52Ser	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
ATOH8	ENST00000716557.1		c.154C>T	p.Pro52Ser	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
ATOH8	ENST00000881377.1		c.154C>T	p.Pro52Ser	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000693

AC:

AN:

230846

AF XY:

0.0000937

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000890

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000591

AC:

AN:

1455540

Hom.:

Cov.:

AF XY:

0.0000566

AC XY:

AN XY:

724288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32354

American (AMR)

AF:

0.000157

AC:

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39112

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51804

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000640

AC:

AN:

1109956

Other (OTH)

AF:

0.0000832

AC:

AN:

60126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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

AF:

0.000191

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00118

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67994

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000234

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.0000336

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.024

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.81

PhyloP100

0.42

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.030

REVEL

Benign

0.086

Sift

Benign

0.14

Sift4G

Benign

0.34

Polyphen

0.0050

Vest4

0.097

MVP

0.31

MPC

0.57

ClinPred

0.043

GERP RS

1.3

PromoterAI

-0.052

Neutral

(source)

Varity_R

0.056

gMVP

0.078

Mutation Taster

=93/7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over