4-93829209-C-T

Variant names:

• chr4-93829209-C-T
• rs200577041
• NM_005172.2:c.283C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005172.2(ATOH1):​c.283C>T​(p.Pro95Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,583,846 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: ATOH1 NM_005172.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.338

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017085135).
• BS2: High AC in GnomAd4 at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH1	NM_005172.2	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 1	ENST00000306011.6	NP_005163.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATOH1	ENST00000306011.6	c.283C>T	p.Pro95Ser	missense_variant	Exon 1 of 1	6	NM_005172.2	ENSP00000302216.4

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000676 AC: 150 AN: 221994 Hom.: 0 AF XY: 0.000766 AC XY: 92 AN XY: 120094

Gnomad AFR exome AF: 0.000347

Gnomad AMR exome AF: 0.000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000483

Gnomad FIN exome AF: 0.0000513

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00113 AC: 1623 AN: 1431542 Hom.: 5 Cov.: 32 AF XY: 0.00109 AC XY: 775 AN XY: 708494

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.000377

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000605

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74458

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000737

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000936 AC: 8

ExAC AF: 0.000546 AC: 66

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283C>T (p.P95S) alteration is located in exon 1 (coding exon 1) of the ATOH1 gene. This alteration results from a C to T substitution at nucleotide position 283, causing the proline (P) at amino acid position 95 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ATOH1-related disorder Benign:1

Sep 15, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Benign	0.76	N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.019
MVP		0.41
MPC		0.62
ClinPred		0.0060	T
GERP RS		2.5
Varity_R		0.052
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs200577041; hg19: chr4-94750360; COSMIC: COSV60037842;