chr4-93829264-C-T

Variant names:

• chr4-93829264-C-T
• rs1205540724
• NM_005172.2:c.338C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005172.2(ATOH1):​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 0.0000269 in 1,598,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: ATOH1 NM_005172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0720
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067744255).
• BS2: High AC in GnomAdExome4 at 42 AD gene.

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.338C>T	p.Ala113Val	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.338C>T	p.Ala113Val	missense	Exon 1 of 1	ENSP00000302216.4	Q92858

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000857 AC: 2 AN: 233296 AF XY: 0.00000789

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: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000290 AC: 42 AN: 1446776 Hom.: 0 Cov.: 32 AF XY: 0.0000306 AC XY: 22 AN XY: 718034

African (AFR) AF: 0.0000300 AC: 1 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24922

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 83854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5484

European-Non Finnish (NFE) AF: 0.0000362 AC: 40 AN: 1103566

Other (OTH) AF: 0.0000168 AC: 1 AN: 59596

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000611 Hom.: 0

Bravo AF: 0.0000113

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	0.070
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	6.6
DANN	Benign	0.92
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.068	T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.072
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.23
Sift	Uncertain	0.016	D
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.033
MVP		0.31
MPC		0.61
ClinPred		0.028	T
GERP RS		-0.85
Varity_R		0.070
gMVP		0.29
Mutation Taster		=98/2	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

dbSNP: rs1205540724; hg19: chr4-94750415;