chr2-85754611-A-C

Variant names:

• chr2-85754611-A-C
• rs781183419
• NM_032827.7:c.422A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032827.7(ATOH8):​c.422A>C​(p.Glu141Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,487,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.300
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33227012).

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.422A>C	p.Glu141Ala	missense	Exon 1 of 3	NP_116216.2	Q96SQ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATOH8	ENST00000306279.4	TSL:1 MANE Select	c.422A>C	p.Glu141Ala	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
	ATOH8	ENST00000716557.1		c.422A>C	p.Glu141Ala	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
	ATOH8	ENST00000881377.1		c.422A>C	p.Glu141Ala	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes AF: 0.0000931 AC: 14 AN: 150442 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.000192

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.0000894 AC: 8 AN: 89516 AF XY: 0.000139

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: 0.000228

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000250 AC: 334 AN: 1336770 Hom.: 0 Cov.: 30 AF XY: 0.000245 AC XY: 161 AN XY: 658234

African (AFR) AF: 0.00 AC: 0 AN: 27758

American (AMR) AF: 0.0000371 AC: 1 AN: 26940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21644

East Asian (EAS) AF: 0.00 AC: 0 AN: 32392

South Asian (SAS) AF: 0.00 AC: 0 AN: 71856

European-Finnish (FIN) AF: 0.000135 AC: 5 AN: 37136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 0.000303 AC: 321 AN: 1058480

Other (OTH) AF: 0.000126 AC: 7 AN: 55454

GnomAD4 genome AF: 0.0000931 AC: 14 AN: 150442 Hom.: 0 Cov.: 33 AF XY: 0.0000953 AC XY: 7 AN XY: 73442

African (AFR) AF: 0.00 AC: 0 AN: 40810

American (AMR) AF: 0.00 AC: 0 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4966

South Asian (SAS) AF: 0.00 AC: 0 AN: 4738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000192 AC: 13 AN: 67574

Other (OTH) AF: 0.000486 AC: 1 AN: 2058

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000269 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T
Eigen	Benign	0.055
Eigen_PC	Benign	-0.023
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.012	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.30
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.24
Sift	Benign	0.18	T
Sift4G	Benign	0.76	T
Polyphen		0.96	P
Vest4		0.30
MutPred		0.17		Gain of methylation at R146 (P = 0.0526)
MVP		0.68
MPC		0.61
ClinPred		0.16	T
GERP RS		3.4
Varity_R		0.097
gMVP		0.29
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs781183419; hg19: chr2-85981734;