3-193648185-T-G

Variant names:

• chr3-193648185-T-G
• rs9831900
• NM_130837.3:c.1935+51T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130837.3(OPA1):​c.1935+51T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.472 in 1,394,268 control chromosomes in the GnomAD database, including 156,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19160 hom., cov: 32)
  • Exomes 𝑓: 0.47 (137462 hom.)
• Consequence: OPA1 NM_130837.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.43
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant optic atrophy, classic form

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• optic atrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• OPA1-related optic atrophy with or without extraocular features

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• Behr syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type)

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal dominant optic atrophy plus syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 3-193648185-T-G is Benign according to our data. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-193648185-T-G is described in CliVar as Benign. Clinvar id is 1258764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1935+51T>G		intron_variant	Intron 20 of 30	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1935+51T>G		intron_variant	Intron 20 of 30	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.496 AC: 75424 AN: 151932 Hom.: 19131 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.472

GnomAD2 exomes AF: 0.469 AC: 113981 AN: 242784 AF XY: 0.466

Gnomad AFR exome AF: 0.575

Gnomad AMR exome AF: 0.421

Gnomad ASJ exome AF: 0.469

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.470

Gnomad OTH exome AF: 0.456

GnomAD4 exome AF: 0.469 AC: 582021 AN: 1242218 Hom.: 137462 Cov.: 17 AF XY: 0.467 AC XY: 293377 AN XY: 628620

African (AFR) AF: 0.578 AC: 16831 AN: 29138

American (AMR) AF: 0.422 AC: 18578 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 11713 AN: 24708

East Asian (EAS) AF: 0.357 AC: 13717 AN: 38370

South Asian (SAS) AF: 0.439 AC: 35680 AN: 81242

European-Finnish (FIN) AF: 0.573 AC: 30320 AN: 52930

Middle Eastern (MID) AF: 0.415 AC: 2231 AN: 5380

European-Non Finnish (NFE) AF: 0.469 AC: 428036 AN: 913462

Other (OTH) AF: 0.470 AC: 24915 AN: 53016

GnomAD4 genome AF: 0.497 AC: 75506 AN: 152050 Hom.: 19160 Cov.: 32 AF XY: 0.497 AC XY: 36928 AN XY: 74320

African (AFR) AF: 0.568 AC: 23539 AN: 41442

American (AMR) AF: 0.443 AC: 6775 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1603 AN: 3468

East Asian (EAS) AF: 0.394 AC: 2041 AN: 5174

South Asian (SAS) AF: 0.425 AC: 2047 AN: 4814

European-Finnish (FIN) AF: 0.572 AC: 6044 AN: 10570

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31823 AN: 67980

Other (OTH) AF: 0.473 AC: 998 AN: 2108

Alfa AF: 0.413 Hom.: 2074

Bravo AF: 0.492

Asia WGS AF: 0.424 AC: 1474 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.43
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs9831900; hg19: chr3-193365974; COSMIC: COSV62478877; COSMIC: COSV62478877;