chr3-193637285-T-C

Variant names:

• chr3-193637285-T-C
• rs166850
• NM_130837.3:c.1035+4T>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+4T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.847 in 1,591,702 control chromosomes in the GnomAD database, including 573,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59465 hom., cov: 29)
  • Exomes 𝑓: 0.84 (513691 hom.)
• Consequence: OPA1 NM_130837.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002301
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.63
• Publications: 46 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: G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.76).
• BP6: Variant 3-193637285-T-C is Benign according to our data. Variant chr3-193637285-T-C is described in ClinVar as Benign. ClinVar VariationId is 95731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.961 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	NM_130837.3	MANE Select	c.1035+4T>C		splice_region intron	N/A	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.981+4T>C		splice_region intron	N/A	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.927+4T>C		splice_region intron	N/A	NP_570848.1	E5KLJ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPA1	ENST00000361510.8	TSL:5 MANE Select	c.1035+4T>C		splice_region intron	N/A	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.981+4T>C		splice_region intron	N/A	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.1050+4T>C		splice_region intron	N/A	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.883 AC: 133851 AN: 151590 Hom.: 59406 Cov.: 29

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.960

Gnomad SAS AF: 0.893

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.877

GnomAD2 exomes AF: 0.870 AC: 217513 AN: 249986 AF XY: 0.868

Gnomad AFR exome AF: 0.971

Gnomad AMR exome AF: 0.894

Gnomad ASJ exome AF: 0.847

Gnomad EAS exome AF: 0.958

Gnomad FIN exome AF: 0.875

Gnomad NFE exome AF: 0.829

Gnomad OTH exome AF: 0.860

GnomAD4 exome AF: 0.844 AC: 1214822 AN: 1439994 Hom.: 513691 Cov.: 25 AF XY: 0.845 AC XY: 606092 AN XY: 717488

African (AFR) AF: 0.973 AC: 32168 AN: 33054

American (AMR) AF: 0.895 AC: 39821 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.845 AC: 21897 AN: 25920

East Asian (EAS) AF: 0.973 AC: 38270 AN: 39340

South Asian (SAS) AF: 0.899 AC: 76533 AN: 85174

European-Finnish (FIN) AF: 0.874 AC: 46473 AN: 53182

Middle Eastern (MID) AF: 0.855 AC: 4887 AN: 5716

European-Non Finnish (NFE) AF: 0.826 AC: 903716 AN: 1093630

Other (OTH) AF: 0.859 AC: 51057 AN: 59472

GnomAD4 genome AF: 0.883 AC: 133970 AN: 151708 Hom.: 59465 Cov.: 29 AF XY: 0.885 AC XY: 65543 AN XY: 74090

African (AFR) AF: 0.969 AC: 40081 AN: 41384

American (AMR) AF: 0.885 AC: 13459 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.841 AC: 2916 AN: 3468

East Asian (EAS) AF: 0.960 AC: 4967 AN: 5176

South Asian (SAS) AF: 0.893 AC: 4275 AN: 4788

European-Finnish (FIN) AF: 0.870 AC: 9087 AN: 10448

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56290 AN: 67944

Other (OTH) AF: 0.878 AC: 1841 AN: 2098

Alfa AF: 0.860 Hom.: 32729

Bravo AF: 0.889

Asia WGS AF: 0.923 AC: 3188 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	3	Autosomal dominant optic atrophy classic form (3)
-	-	1	Abortive cerebellar ataxia (1)
-	-	1	Mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) (1)
-	-	1	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.48
PhyloP100		1.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.0020
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: rs166850; hg19: chr3-193355074;