2-85754454-G-C

Position:

• chr2-85754454-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032827.7(ATOH8):​c.265G>C​(p.Gly89Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000739 in 1,352,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32298407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATOH8	NM_032827.7	c.265G>C	p.Gly89Arg	missense_variant	1/3	ENST00000306279.4	NP_116216.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATOH8	ENST00000306279.4	c.265G>C	p.Gly89Arg	missense_variant	1/3	1	NM_032827.7	ENSP00000304676	P1
ATOH8	ENST00000469442.5	n.519+2592G>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.39e-7 AC: 1 AN: 1352496 Hom.: 0 Cov.: 30 AF XY: 0.00000150 AC XY: 1 AN XY: 666868

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: 9.36e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2023

The c.265G>C (p.G89R) alteration is located in exon 1 (coding exon 1) of the ATOH8 gene. This alteration results from a G to C substitution at nucleotide position 265, causing the glycine (G) at amino acid position 89 to be replaced by an arginine (R). 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	0.14
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.0068	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.17	T
Polyphen		0.39	B
Vest4		0.43
MutPred		0.22		Gain of methylation at G89 (P = 0.0071);
MVP		0.19
MPC		0.88
ClinPred		0.59	D
GERP RS		0.57
Varity_R		0.17
gMVP		0.14

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

Other links and lift over

dbSNP: rs747123720; hg19: chr2-85981577;