Genetic Variant OPA1:c.-144T>G (chr3-193593234-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_130837.3(OPA1):c.-144T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000737 in 542,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

OPA1
NM_130837.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.03

Publications

0 publications found

Variant links:

Genes affected

OPA1 (HGNC:8140): (OPA1 mitochondrial dynamin like GTPase) The protein encoded by this gene is a nuclear-encoded mitochondrial protein with similarity to dynamin-related GTPases. The encoded protein localizes to the inner mitochondrial membrane and helps regulate mitochondrial stability and energy output. This protein also sequesters cytochrome c. Mutations in this gene have been associated with optic atrophy type 1, which is a dominantly inherited optic neuropathy resulting in progressive loss of visual acuity, leading in many cases to legal blindness. [provided by RefSeq, Aug 2017]

OPA1 links:

ATP13A4 (HGNC:25422): (ATPase 13A4) Predicted to enable ATPase-coupled cation transmembrane transporter activity. Predicted to be involved in cellular calcium ion homeostasis. Predicted to be located in endoplasmic reticulum membrane and endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ATP13A4 links:

ENSG00000293063 (HGNC:):

ENSG00000293063 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.14).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130837.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OPA1	NM_130837.3	MANE Select	c.-144T>G	5_prime_UTR	Exon 1 of 31	NP_570850.2	O60313-10
OPA1	NM_130836.3		c.-144T>G	5_prime_UTR	Exon 1 of 30	NP_570849.2	O60313-2
OPA1	NM_130835.3		c.-144T>G	5_prime_UTR	Exon 1 of 30	NP_570848.1	E5KLJ9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
OPA1	ENST00000361510.8	TSL:5 MANE Select	c.-144T>G	5_prime_UTR	Exon 1 of 31	ENSP00000355324.2	O60313-10
OPA1	ENST00000361908.8	TSL:1	c.-144T>G	5_prime_UTR	Exon 1 of 30	ENSP00000354681.3	O60313-2
OPA1	ENST00000968586.1		c.-144T>G	5_prime_UTR	Exon 1 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000737

AC:

AN:

542686

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

279264

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

12522

American (AMR)

AF:

0.00

AC:

AN:

14956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12990

East Asian (EAS)

AF:

0.00

AC:

AN:

27144

South Asian (SAS)

AF:

0.00

AC:

AN:

40004

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2040

European-Non Finnish (NFE)

AF:

0.0000109

AC:

AN:

368012

Other (OTH)

AF:

0.00

AC:

AN:

27758

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.0

PromoterAI

-0.22

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over