rs35540805

Variant names:

• chr3-193667258-C-T
• rs35540805
• NM_130837.3:c.2961C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-193667258-C-T
• chr3-193667258-C-A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_130837.3(OPA1):​c.2961C>T​(p.Arg987Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,586,394 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (32 hom.)
• Consequence: OPA1 NM_130837.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.111
• Publications: 7 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

ENSG00000306963 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.131).
• BP6: Variant 3-193667258-C-T is Benign according to our data. Variant chr3-193667258-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.111 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00742 (1130/152240) while in subpopulation AFR AF = 0.022 (912/41540). AF 95% confidence interval is 0.0208. There are 10 homozygotes in GnomAd4. There are 545 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR,SD gene

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.2961C>T	p.Arg987Arg	synonymous	Exon 29 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.2907C>T	p.Arg969Arg	synonymous	Exon 28 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.2853C>T	p.Arg951Arg	synonymous	Exon 28 of 30	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.2961C>T	p.Arg987Arg	synonymous	Exon 29 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.2907C>T	p.Arg969Arg	synonymous	Exon 28 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.2976C>T	p.Arg992Arg	synonymous	Exon 30 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.00742 AC: 1128 AN: 152122 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00871

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00447 AC: 1125 AN: 251468 AF XY: 0.00411

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0204

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00202 AC: 2900 AN: 1434154 Hom.: 32 Cov.: 25 AF XY: 0.00218 AC XY: 1558 AN XY: 715520

African (AFR) AF: 0.0205 AC: 674 AN: 32890

American (AMR) AF: 0.00315 AC: 141 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00343 AC: 89 AN: 25972

East Asian (EAS) AF: 0.0222 AC: 879 AN: 39542

South Asian (SAS) AF: 0.00867 AC: 743 AN: 85706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00210 AC: 12 AN: 5708

European-Non Finnish (NFE) AF: 0.000121 AC: 131 AN: 1086830

Other (OTH) AF: 0.00389 AC: 231 AN: 59410

GnomAD4 genome AF: 0.00742 AC: 1130 AN: 152240 Hom.: 10 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74454

African (AFR) AF: 0.0220 AC: 912 AN: 41540

American (AMR) AF: 0.00353 AC: 54 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.0185 AC: 96 AN: 5184

South Asian (SAS) AF: 0.00872 AC: 42 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00501 Hom.: 5

Bravo AF: 0.00824

Asia WGS AF: 0.0220 AC: 78 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Autosomal dominant optic atrophy classic form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	4.6
DANN	Benign	0.51
PhyloP100		0.11
PromoterAI		0.0023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35540805; hg19: chr3-193385047;