dbSNP rs753615804: ATOH8:p.Pro85Thr (chr2-85754442-C-A) – 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_032827.7(ATOH8):c.253C>A(p.Pro85Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,702 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. 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. P85S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.307

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:

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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=0.13055503).

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.253C>A	p.Pro85Thr	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.253C>A	p.Pro85Thr	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
ATOH8	ENST00000716557.1		c.253C>A	p.Pro85Thr	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
ATOH8	ENST00000881377.1		c.253C>A	p.Pro85Thr	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.33e-7

AC:

AN:

1364702

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

673332

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27166

American (AMR)

AF:

0.0000329

AC:

AN:

30420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20664

East Asian (EAS)

AF:

0.00

AC:

AN:

34982

South Asian (SAS)

AF:

0.00

AC:

AN:

72612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4956

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1071652

Other (OTH)

AF:

0.00

AC:

AN:

55832

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.042

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.13

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.69

PhyloP100

0.31

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.61

REVEL

Benign

0.12

Sift

Benign

0.068

Sift4G

Benign

0.10

Polyphen

0.028

Vest4

0.16

MutPred

0.14

Gain of phosphorylation at P85 (P = 0.0222)

MVP

0.20

MPC

0.66

ClinPred

0.13

GERP RS

2.4

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.072

gMVP

0.13

Mutation Taster

=94/6

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over