NM_145178.4:c.136A>C

Variant names:

• chr10-68231542-T-G
• rs587777666
• NM_145178.4:c.136A>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_145178.4(ATOH7):​c.136A>C​(p.Asn46His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N46S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATOH7 NM_145178.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• 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: Pathogenic. The variant received 10 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, 13 uncertain in NM_145178.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.943
• PP5: Variant 10-68231542-T-G is Pathogenic according to our data. Variant chr10-68231542-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 144067.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATOH7	NM_145178.4	c.136A>C	p.Asn46His	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.136A>C	p.Asn46His	missense_variant	Exon 1 of 1	6	NM_145178.4	ENSP00000362777.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Persistent hyperplastic primary vitreous, autosomal recessive Pathogenic:1

Aug 15, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.71		Loss of catalytic residue at N46 (P = 0.1856);
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.99
gMVP		0.86
Mutation Taster		=35/65	disease causing (ClinVar)

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: rs587777666; hg19: chr10-69991299;