chr4-93829059-G-C

Variant names:

• chr4-93829059-G-C
• rs145839632
• NM_005172.2:c.133G>C

Variant summary

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

The NM_005172.2(ATOH1):​c.133G>C​(p.Glu45Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,613,736 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E45E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ATOH1 NM_005172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 1 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=0.0050924122).
• BS2: High AC in GnomAd4 at 37 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.133G>C	p.Glu45Gln	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.133G>C	p.Glu45Gln	missense	Exon 1 of 1	ENSP00000302216.4	Q92858

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152076 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000412 AC: 103 AN: 250140 AF XY: 0.000384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00757

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1461660 Hom.: 1 Cov.: 32 AF XY: 0.000202 AC XY: 147 AN XY: 727146

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00796 AC: 208 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111978

Other (OTH) AF: 0.000563 AC: 34 AN: 60388

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152076 Hom.: 1 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74276

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00318 AC: 1 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000811 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000313 AC: 38

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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	-0.15	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.0037
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0051	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.8	L
PhyloP100		4.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.32
Sift	Benign	0.045	D
Sift4G	Uncertain	0.033	D
Polyphen		0.016	B
Vest4		0.049
MVP		0.82
MPC		0.79
ClinPred		0.025	T
GERP RS		4.5
PromoterAI		-0.016	Neutral
Varity_R		0.099
gMVP		0.45
Mutation Taster		=84/16	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: rs145839632; hg19: chr4-94750210;