10-68231532-T-C

Variant names:

• chr10-68231532-T-C
• rs587777664
• NM_145178.4:c.146A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_145178.4(ATOH7):​c.146A>G​(p.Glu49Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000168 in 1,189,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E49V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ATOH7 NM_145178.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.18
• Publications: 3 publications found

Genes affected

ATOH7 (HGNC:13907): (atonal bHLH transcription factor 7) This intronless gene encodes a member of the basic helix-loop-helix family of transcription factors, with similarity to Drosophila atonal gene that controls photoreceptor development. Studies in mice suggest that this gene plays a central role in retinal ganglion cell and optic nerve formation. Mutations in this gene are associated with nonsyndromic congenital retinal nonattachment. [provided by RefSeq, Dec 2011]

ATOH7 Gene-Disease associations (from GenCC):

• persistent hyperplastic primary vitreous, autosomal recessive

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• persistent hyperplastic primary vitreous

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• anterior segment dysgenesis 7

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_145178.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-68231532-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 144065.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.30531 (below the threshold of 3.09). Trascript score misZ: -1.2226 (below the threshold of 3.09). GenCC associations: The gene is linked to persistent hyperplastic primary vitreous, autosomal recessive, persistent hyperplastic primary vitreous, anterior segment dysgenesis 7.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH7	NM_145178.4	c.146A>G	p.Glu49Gly	missense_variant	Exon 1 of 1	ENST00000373673.5	NP_660161.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATOH7	ENST00000373673.5	c.146A>G	p.Glu49Gly	missense_variant	Exon 1 of 1	6	NM_145178.4	ENSP00000362777.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1189970 Hom.: 0 Cov.: 30 AF XY: 0.00000348 AC XY: 2 AN XY: 575242

African (AFR) AF: 0.00 AC: 0 AN: 25346

American (AMR) AF: 0.00 AC: 0 AN: 18894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16734

East Asian (EAS) AF: 0.00 AC: 0 AN: 30568

South Asian (SAS) AF: 0.00 AC: 0 AN: 36780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4748

European-Non Finnish (NFE) AF: 0.00000207 AC: 2 AN: 968154

Other (OTH) AF: 0.00 AC: 0 AN: 47246

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H
PhyloP100		6.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.57	P
Vest4		0.75
MutPred		0.75		Gain of methylation at R48 (P = 0.0363);
MVP		0.95
MPC		2.0
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.97
gMVP		0.87
Mutation Taster		=35/65	disease causing

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: rs587777664; hg19: chr10-69991289;