rs959307736

Variant names:

• chr2-85754527-C-T
• rs959307736
• NM_032827.7:c.338C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032827.7(ATOH8):​c.338C>T​(p.Ala113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,431,000 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 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: ATOH8 NM_032827.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.728
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27274263).

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.338C>T	p.Ala113Val	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.338C>T	p.Ala113Val	missense	Exon 1 of 3	ENSP00000304676.3	Q96SQ7-1
	ATOH8	ENST00000716557.1		c.338C>T	p.Ala113Val	missense	Exon 1 of 3	ENSP00000520563.1	Q96SQ7-1
	ATOH8	ENST00000881377.1		c.338C>T	p.Ala113Val	missense	Exon 1 of 3	ENSP00000551436.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000902 AC: 3 AN: 33256 AF XY: 0.0000532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000455

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000469 AC: 6 AN: 1278780 Hom.: 0 Cov.: 30 AF XY: 0.00000320 AC XY: 2 AN XY: 625080

African (AFR) AF: 0.00 AC: 0 AN: 24672

American (AMR) AF: 0.000235 AC: 4 AN: 16986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18378

East Asian (EAS) AF: 0.0000329 AC: 1 AN: 30432

South Asian (SAS) AF: 0.00 AC: 0 AN: 62284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3946

European-Non Finnish (NFE) AF: 9.65e-7 AC: 1 AN: 1035852

Other (OTH) AF: 0.00 AC: 0 AN: 52892

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74420

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.000131 AC: 2 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

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	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.73
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.28
Sift	Benign	0.061	T
Sift4G	Benign	0.39	T
Polyphen		0.18	B
Vest4		0.30
MutPred		0.31		Loss of helix (P = 0.0093)
MVP		0.39
MPC		0.62
ClinPred		0.10	T
GERP RS		2.7
Varity_R		0.078
gMVP		0.17
Mutation Taster		=91/9	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: rs959307736; hg19: chr2-85981650;