3-193668749-C-T

Variant names:

• chr3-193668749-C-T
• rs414237
• NM_130837.3:c.2983+1469C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130837.3(OPA1):​c.2983+1469C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.678 in 1,265,718 control chromosomes in the GnomAD database, including 292,620 homozygotes. 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: 𝑓 0.71 (38502 hom., cov: 31)
  • Exomes 𝑓: 0.67 (254118 hom.)
• Consequence: OPA1 NM_130837.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 5 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.8 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.2983+1469C>T		intron	N/A	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.2929+1469C>T		intron	N/A	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.2875+1469C>T		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.2983+1469C>T		intron	N/A	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.2929+1469C>T		intron	N/A	ENSP00000354681.3	O60313-2
	OPA1	ENST00000392436.7	TSL:3	c.*334C>T		3_prime_UTR	Exon 28 of 28	ENSP00000376231.3	C9JMB8

Frequencies

GnomAD3 genomes AF: 0.708 AC: 107561 AN: 151856 Hom.: 38460 Cov.: 31

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.781

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.674

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.720

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.704

GnomAD4 exome AF: 0.674 AC: 750380 AN: 1113742 Hom.: 254118 Cov.: 38 AF XY: 0.678 AC XY: 362801 AN XY: 535014

African (AFR) AF: 0.772 AC: 18590 AN: 24074

American (AMR) AF: 0.760 AC: 11579 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.684 AC: 8838 AN: 12914

East Asian (EAS) AF: 0.731 AC: 13380 AN: 18296

South Asian (SAS) AF: 0.828 AC: 49936 AN: 60314

European-Finnish (FIN) AF: 0.730 AC: 11058 AN: 15150

Middle Eastern (MID) AF: 0.722 AC: 2068 AN: 2864

European-Non Finnish (NFE) AF: 0.657 AC: 605509 AN: 922244

Other (OTH) AF: 0.690 AC: 29422 AN: 42658

GnomAD4 genome AF: 0.708 AC: 107664 AN: 151976 Hom.: 38502 Cov.: 31 AF XY: 0.715 AC XY: 53098 AN XY: 74276

African (AFR) AF: 0.759 AC: 31451 AN: 41448

American (AMR) AF: 0.743 AC: 11347 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.674 AC: 2339 AN: 3468

East Asian (EAS) AF: 0.725 AC: 3731 AN: 5144

South Asian (SAS) AF: 0.822 AC: 3959 AN: 4818

European-Finnish (FIN) AF: 0.726 AC: 7659 AN: 10548

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44777 AN: 67964

Other (OTH) AF: 0.705 AC: 1485 AN: 2106

Alfa AF: 0.671 Hom.: 55512

Bravo AF: 0.710

Asia WGS AF: 0.764 AC: 2655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.010
DANN	Benign	0.25
PhyloP100		-2.0
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: rs414237; hg19: chr3-193386538;