rs863224140

Variant names:

• chr3-193614797-TTTCACGAAGCATTTATCA-T
• rs863224140
• NM_130837.3:c.113_130delGAAGCATTTATCATTCAC

Your query was ambiguous. Multiple possible variants found:

• chr3-193614797-TTTCACGAAGCATTTATCA-T
• chr3-193614797-TTTCACGAAGCATTTATCA-TTTCACGAAGCATTTATCATTCACGAAGCATTTATCA

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_130837.3(OPA1):​c.113_130delGAAGCATTTATCATTCAC​(p.Arg38_Ser43del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00222 in 1,613,980 control chromosomes in the GnomAD database, including 10 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (10 hom.)
• Consequence: OPA1 NM_130837.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 7.07
• Publications: 2 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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_130837.3.
• BP6: Variant 3-193614797-TTTCACGAAGCATTTATCA-T is Benign according to our data. Variant chr3-193614797-TTTCACGAAGCATTTATCA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214916.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00135 (205/152336) while in subpopulation NFE AF = 0.0021 (143/68028). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 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.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 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.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.113_130delGAAGCATTTATCATTCAC	p.Arg38_Ser43del	disruptive_inframe_deletion	Exon 2 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00174 AC: 432 AN: 248960 AF XY: 0.00169

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00231 AC: 3372 AN: 1461644 Hom.: 10 AF XY: 0.00220 AC XY: 1597 AN XY: 727138

African (AFR) AF: 0.000299 AC: 10 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00188 AC: 49 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00397 AC: 212 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00271 AC: 3008 AN: 1111792

Other (OTH) AF: 0.00142 AC: 86 AN: 60386

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00136 AC XY: 101 AN XY: 74486

African (AFR) AF: 0.000337 AC: 14 AN: 41574

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000672 Hom.: 1

Bravo AF: 0.00121

EpiCase AF: 0.00218

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	not specified (2)
-	1	-	Abortive cerebellar ataxia (1)
-	-	1	OPA1-related disorder (1)
-	1	-	Optic atrophy (1)
-	1	-	Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy (1)
-	1	-	Ptosis;C0151786:Muscle weakness;C0241005:Elevated circulating creatine kinase concentration;C0476403:EMG abnormality;C0813217:Hypomimic face;C1836156:Progressive proximal muscle weakness;C2711227:Hepatic steatosis;C4021726:EMG: myopathic abnormalities;C4025576:EMG: myotonic runs (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=48/152	disease causing (long InDel)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863224140; hg19: chr3-193332586;