2-85754643-C-T

Variant names:

• chr2-85754643-C-T
• NM_032827.7:c.454C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032827.7(ATOH8):​c.454C>T​(p.Pro152Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.553

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH8	NM_032827.7	c.454C>T	p.Pro152Ser	missense_variant	Exon 1 of 3	ENST00000306279.4	NP_116216.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATOH8	ENST00000306279.4	c.454C>T	p.Pro152Ser	missense_variant	Exon 1 of 3	1	NM_032827.7	ENSP00000304676.3
ATOH8	ENST00000469442.5	n.519+2781C>T		intron_variant	Intron 1 of 2	2
ATOH8	ENST00000463422.5	n.-4C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1370588 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 675934

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.454C>T (p.P152S) 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 454, causing the proline (P) at amino acid position 152 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	-0.0098	T
MutationAssessor	Benign	0.46	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.29
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.39
MutPred		0.28		Gain of phosphorylation at P152 (P = 0.0213);
MVP		0.67
MPC		0.64
ClinPred		0.54	D
GERP RS		3.6
Varity_R		0.087
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-85981766;