chr4-93829113-G-A

Variant names:

• chr4-93829113-G-A
• NM_005172.2:c.187G>A

Variant summary

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

The NM_005172.2(ATOH1):​c.187G>A​(p.Ala63Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATOH1 NM_005172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• Publications: 0 publications found

Genes affected

ATOH1 (HGNC:797): (atonal bHLH transcription factor 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in neuron differentiation; positive regulation of neuron differentiation; and regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including generation of neurons; inner ear morphogenesis; and positive regulation of inner ear auditory receptor cell differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ATOH1 Gene-Disease associations (from GenCC):

• hearing loss, autosomal dominant 89

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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=0.3648302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005172.2. 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
	ATOH1	NM_005172.2	MANE Select	c.187G>A	p.Ala63Thr	missense	Exon 1 of 1	NP_005163.1	Q92858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATOH1	ENST00000306011.6	TSL:6 MANE Select	c.187G>A	p.Ala63Thr	missense	Exon 1 of 1	ENSP00000302216.4	Q92858

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457282 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724390

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109302

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 33

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	0.17
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.36	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.18
MutPred		0.24		Loss of glycosylation at S58 (P = 0.0191)
MVP		0.76
MPC		1.1
ClinPred		0.92	D
GERP RS		4.2
PromoterAI		-0.021	Neutral
Varity_R		0.31
gMVP		0.68
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr4-94750264;