chr2-85754256-C-T

Variant names:

• chr2-85754256-C-T
• rs560944173
• NM_032827.7:c.67C>T

Variant summary

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

The NM_032827.7(ATOH8):​c.67C>T​(p.Leu23Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.628

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=0.29233843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH8	NM_032827.7	c.67C>T	p.Leu23Phe	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.67C>T	p.Leu23Phe	missense_variant	Exon 1 of 3	1	NM_032827.7	ENSP00000304676.3
ATOH8	ENST00000469442.5	n.519+2394C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000421 AC: 1 AN: 237432 Hom.: 0 AF XY: 0.00000763 AC XY: 1 AN XY: 131018

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: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67C>T (p.L23F) 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 67, causing the leucine (L) at amino acid position 23 to be replaced by a phenylalanine (F). 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	0.21
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.034	D
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Uncertain	0.019	D
Sift4G	Benign	0.21	T
Polyphen		0.99	D
Vest4		0.20
MutPred		0.26		Gain of methylation at K24 (P = 0.0372);
MVP		0.34
MPC		1.5
ClinPred		0.74	D
GERP RS		2.1
Varity_R		0.20
gMVP		0.060

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: rs560944173; hg19: chr2-85981379;