rs779375399

Variant names:

• chr3-193626119-C-A
• rs779375399
• NM_130837.3:c.706C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-193626119-C-A
• chr3-193626119-C-G
• chr3-193626119-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_130837.3(OPA1):​c.706C>A​(p.Gln236Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q236R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: OPA1 NM_130837.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 7.82
• Publications: 0 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-AS1 (HGNC:40421): (OPA1 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 3-193626119-C-A is Benign according to our data. Variant chr3-193626119-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586199.

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.706C>A	p.Gln236Lys	missense	Exon 7 of 31	NP_570850.2	O60313-10
	OPA1	NM_130836.3		c.652C>A	p.Gln218Lys	missense	Exon 6 of 30	NP_570849.2	O60313-2
	OPA1	NM_130835.3		c.598C>A	p.Gln200Lys	missense	Exon 6 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.706C>A	p.Gln236Lys	missense	Exon 7 of 31	ENSP00000355324.2	O60313-10
	OPA1	ENST00000361908.8	TSL:1	c.652C>A	p.Gln218Lys	missense	Exon 6 of 30	ENSP00000354681.3	O60313-2
	OPA1	ENST00000968586.1		c.706C>A	p.Gln236Lys	missense	Exon 7 of 32	ENSP00000638645.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251422 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.31	D
PhyloP100		7.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.40
Sift	Benign	0.80	T
Sift4G	Benign	0.96	T
Polyphen		0.71	P
Vest4		0.64
MutPred		0.33		Gain of ubiquitination at Q236 (P = 0.0101)
MVP		0.73
MPC		0.19
ClinPred		0.55	D
GERP RS		5.7
gMVP		0.55
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: -27

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

Other links and lift over

dbSNP: rs779375399; hg19: chr3-193343908;