2-175178369-A-G

Variant names:

• chr2-175178369-A-G
• rs8106
• NM_001689.5:c.348T>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001689.5(ATP5MC3):​c.348T>C​(p.Tyr116Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0618 in 1,611,672 control chromosomes in the GnomAD database, including 3,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.045 (225 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3356 hom.)
• Consequence: ATP5MC3 NM_001689.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.319
• Publications: 15 publications found

Genes affected

ATP5MC3 (HGNC:843): (ATP synthase membrane subunit c locus 3) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene is one of three genes that encode subunit c of the proton channel. Each of the three genes have distinct mitochondrial import sequences but encode the identical mature protein. Alternatively spliced transcript variants encoding different proteins have been identified. [provided by RefSeq, Jun 2010]

ATP5MC3 Gene-Disease associations (from GenCC):

• dystonia, early-onset, and/or spastic paraplegia

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 2-175178369-A-G is Benign according to our data. Variant chr2-175178369-A-G is described in ClinVar as Benign. ClinVar VariationId is 559376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.319 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001689.5. 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
	ATP5MC3	NM_001689.5	MANE Select	c.348T>C	p.Tyr116Tyr	synonymous	Exon 5 of 5	NP_001680.1	P48201
	ATP5MC3	NM_001002258.5		c.348T>C	p.Tyr116Tyr	synonymous	Exon 4 of 4	NP_001002258.1	P48201
	ATP5MC3	NM_001190329.2		c.*684T>C		3_prime_UTR	Exon 4 of 4	NP_001177258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5MC3	ENST00000284727.9	TSL:1 MANE Select	c.348T>C	p.Tyr116Tyr	synonymous	Exon 5 of 5	ENSP00000284727.4	P48201
	ATP5MC3	ENST00000392541.3	TSL:1	c.348T>C	p.Tyr116Tyr	synonymous	Exon 4 of 4	ENSP00000376324.3	P48201
	ATP5MC3	ENST00000941362.1		c.354T>C	p.Tyr118Tyr	synonymous	Exon 5 of 5	ENSP00000611421.1

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6823 AN: 152188 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0280

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0300

Gnomad FIN AF: 0.0887

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0485 AC: 12037 AN: 248440 AF XY: 0.0492

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0269

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0889

Gnomad NFE exome AF: 0.0630

Gnomad OTH exome AF: 0.0450

GnomAD4 exome AF: 0.0635 AC: 92720 AN: 1459366 Hom.: 3356 Cov.: 31 AF XY: 0.0625 AC XY: 45347 AN XY: 725928

African (AFR) AF: 0.00955 AC: 318 AN: 33302

American (AMR) AF: 0.0391 AC: 1729 AN: 44228

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 732 AN: 26078

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39614

South Asian (SAS) AF: 0.0325 AC: 2780 AN: 85652

European-Finnish (FIN) AF: 0.0843 AC: 4495 AN: 53294

Middle Eastern (MID) AF: 0.0203 AC: 117 AN: 5756

European-Non Finnish (NFE) AF: 0.0714 AC: 79335 AN: 1111154

Other (OTH) AF: 0.0532 AC: 3209 AN: 60288

GnomAD4 genome AF: 0.0448 AC: 6826 AN: 152306 Hom.: 225 Cov.: 32 AF XY: 0.0449 AC XY: 3347 AN XY: 74488

African (AFR) AF: 0.0123 AC: 510 AN: 41564

American (AMR) AF: 0.0323 AC: 494 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 97 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4828

European-Finnish (FIN) AF: 0.0887 AC: 941 AN: 10608

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0669 AC: 4548 AN: 68022

Other (OTH) AF: 0.0369 AC: 78 AN: 2116

Alfa AF: 0.0577 Hom.: 529

Bravo AF: 0.0391

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0571

EpiControl AF: 0.0545

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.1
DANN	Benign	0.79
PhyloP100		0.32
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=94/6	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: rs8106; hg19: chr2-176043097;