3-193637313-T-C

Variant names:

• chr3-193637313-T-C
• rs10451941
• NM_130837.3:c.1035+32T>C

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.1035+32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,412,594 control chromosomes in the GnomAD database, including 131,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14101 hom., cov: 30)
  • Exomes 𝑓: 0.43 (117440 hom.)
• Consequence: OPA1 NM_130837.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0240
• Publications: 32 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-193637313-T-C is Benign according to our data. Variant chr3-193637313-T-C is described in ClinVar as Benign. ClinVar VariationId is 95730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPA1	NM_130837.3	c.1035+32T>C		intron_variant	Intron 10 of 30	ENST00000361510.8	NP_570850.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPA1	ENST00000361510.8	c.1035+32T>C		intron_variant	Intron 10 of 30	5	NM_130837.3	ENSP00000355324.2

Frequencies

GnomAD3 genomes AF: 0.428 AC: 64673 AN: 151178 Hom.: 14087 Cov.: 30

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.424 AC: 105597 AN: 249148 AF XY: 0.420

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.332

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.437

Gnomad OTH exome AF: 0.424

GnomAD4 exome AF: 0.428 AC: 539842 AN: 1261294 Hom.: 117440 Cov.: 17 AF XY: 0.426 AC XY: 271417 AN XY: 637656

African (AFR) AF: 0.417 AC: 12253 AN: 29360

American (AMR) AF: 0.400 AC: 17652 AN: 44132

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 10561 AN: 24730

East Asian (EAS) AF: 0.285 AC: 10953 AN: 38416

South Asian (SAS) AF: 0.377 AC: 30598 AN: 81164

European-Finnish (FIN) AF: 0.544 AC: 28788 AN: 52924

Middle Eastern (MID) AF: 0.370 AC: 1988 AN: 5366

European-Non Finnish (NFE) AF: 0.434 AC: 404460 AN: 931602

Other (OTH) AF: 0.421 AC: 22589 AN: 53600

GnomAD4 genome AF: 0.428 AC: 64731 AN: 151300 Hom.: 14101 Cov.: 30 AF XY: 0.430 AC XY: 31745 AN XY: 73878

African (AFR) AF: 0.412 AC: 16981 AN: 41224

American (AMR) AF: 0.411 AC: 6230 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1451 AN: 3460

East Asian (EAS) AF: 0.331 AC: 1709 AN: 5156

South Asian (SAS) AF: 0.374 AC: 1790 AN: 4792

European-Finnish (FIN) AF: 0.541 AC: 5598 AN: 10348

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29529 AN: 67868

Other (OTH) AF: 0.416 AC: 866 AN: 2084

Alfa AF: 0.427 Hom.: 6734

Bravo AF: 0.420

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

This variant is associated with the following publications: (PMID: 19581274, 11810296)

not specified Benign:1

Feb 22, 2013

Eurofins Ntd Llc (ga)

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	-0.60
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		0.024
Mutation Taster		=46/54	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: rs10451941; hg19: chr3-193355102; COSMIC: COSV62479516; COSMIC: COSV62479516;