Genetic Variant NM_032827.7:c.217C>A (chr2-85754406-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032827.7(ATOH8):c.217C>A(p.Pro73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000447 in 1,566,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 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: 0.0000035 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.872

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.217C>A	p.Pro73Thr	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.217C>A	p.Pro73Thr	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
ATOH8	ENST00000716557.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
ATOH8	ENST00000881377.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151992

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000532

AC:

AN:

188018

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000362

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000354

AC:

AN:

1414368

Hom.:

Cov.:

AF XY:

0.00000428

AC XY:

AN XY:

701394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28998

American (AMR)

AF:

0.0000256

AC:

AN:

39018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23896

East Asian (EAS)

AF:

0.00

AC:

AN:

36124

South Asian (SAS)

AF:

0.00

AC:

AN:

81380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1091178

Other (OTH)

AF:

0.00

AC:

AN:

57936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67926

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.0000364

Hom.:

Bravo

AF:

0.0000151

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

0.061

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.63

M_CAP

Pathogenic

0.41

MetaRNN

Benign

0.085

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.0

PhyloP100

-0.87

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.24

REVEL

Benign

0.19

Sift

Benign

0.039

Sift4G

Benign

0.91

Polyphen

0.0050

Vest4

0.15

MutPred

0.30

Gain of glycosylation at P73 (P = 0.0086)

MVP

0.20

MPC

0.63

ClinPred

0.049

GERP RS

0.52

PromoterAI

0.072

Neutral

(source)

Varity_R

0.045

gMVP

0.13

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -4

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over