2-85754475-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032827.7(ATOH8):​c.286C>T​(p.Arg96Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,459,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

ATOH8
NM_032827.7 missense

Scores

2
3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.356
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20008472).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ATOH8NM_032827.7 linkc.286C>T p.Arg96Cys missense_variant Exon 1 of 3 ENST00000306279.4 NP_116216.2 Q96SQ7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATOH8ENST00000306279.4 linkc.286C>T p.Arg96Cys missense_variant Exon 1 of 3 1 NM_032827.7 ENSP00000304676.3 Q96SQ7-1
ATOH8ENST00000469442.5 linkn.519+2613C>T intron_variant Intron 1 of 2 2
ATOH8ENST00000463422.5 linkn.-172C>T upstream_gene_variant 1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151992
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000284
AC:
2
AN:
70420
Hom.:
0
AF XY:
0.0000248
AC XY:
1
AN XY:
40324
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000584
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000535
AC:
70
AN:
1307554
Hom.:
0
Cov.:
29
AF XY:
0.0000499
AC XY:
32
AN XY:
640886
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000659
Gnomad4 OTH exome
AF:
0.0000186
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
151992
Hom.:
0
Cov.:
33
AF XY:
0.0000539
AC XY:
4
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000142
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.00000948
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Sep 01, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.286C>T (p.R96C) alteration is located in exon 1 (coding exon 1) of the ATOH8 gene. This alteration results from a C to T substitution at nucleotide position 286, causing the arginine (R) at amino acid position 96 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.020
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
17
DANN
Uncertain
1.0
DEOGEN2
Benign
0.066
T
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.43
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.74
T
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.20
T
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
0.69
N
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.28
Sift
Uncertain
0.0020
D
Sift4G
Benign
0.14
T
Polyphen
0.98
D
Vest4
0.13
MutPred
0.19
Loss of methylation at R96 (P = 0.0198);
MVP
0.28
MPC
1.1
ClinPred
0.53
D
GERP RS
1.5
Varity_R
0.14
gMVP
0.17

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.

Other links and lift over

dbSNP: rs770122243; hg19: chr2-85981598; API