Genetic Variant ATOH8:p.Pro159Leu (chr2-85754665-C-T) – 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.476C>T(p.Pro159Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,954 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P159R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.58

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 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.476C>T	p.Pro159Leu	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.476C>T	p.Pro159Leu	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
ATOH8	ENST00000463422.5	TSL:1	n.19C>T		non_coding_transcript_exon	Exon 1 of 3
ATOH8	ENST00000716557.1		c.476C>T	p.Pro159Leu	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

150822

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

7.18e-7

AC:

AN:

1392954

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687942

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31796

American (AMR)

AF:

0.00

AC:

AN:

34862

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23382

East Asian (EAS)

AF:

0.00

AC:

AN:

37036

South Asian (SAS)

AF:

0.00

AC:

AN:

78538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079222

Other (OTH)

AF:

0.00

AC:

AN:

57640

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

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

Cov.:

ExAC

AF:

0.0000105

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

0.11

Eigen_PC

Benign

0.043

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.49

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

0.90

PhyloP100

2.6

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.058

Polyphen

1.0

Vest4

0.38

MutPred

0.33

Loss of glycosylation at P159 (P = 0.0276)

MVP

0.44

MPC

1.5

ClinPred

0.97

GERP RS

3.6

Varity_R

0.27

gMVP

0.32

Mutation Taster

=95/5

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over