M-8548-T-C

Position:

• chrM-8548-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The ENST00000361899.2(MT-ATP6):​c.22T>C​(p.Ser8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. S8S) has been classified as Uncertain significance.

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 21)
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Benign 0.086
• Clinical Significance: Benign criteria provided, single submitter B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: 2.10

Genes affected

ATP6 (HGNC:):

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.08619702 < 0.5 .
• BP6: Variant M-8548-T-C is Benign according to our data. Variant chrM-8548-T-C is described in ClinVar as [Benign]. Clinvar id is 692895.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomadMitoHomoplasmic at 20

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	ATP6.1	c.22T>C	p.Ser8Pro	missense_variant	1/1		YP_003024031.1
ATP8	ATP8.1	c.183T>C	p.Leu61=	synonymous_variant	1/1		YP_003024030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.22T>C	p.Ser8Pro	missense_variant	1/1			ENSP00000354632	P1
MT-ATP8	ENST00000361851.1	c.183T>C	p.Leu61=	synonymous_variant	1/1			ENSP00000355265	P1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.00030 AC: 21

Gnomad homoplasmic AF: 0.00035 AC: 20 AN: 56429

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56429

Alfa AF: 0.000668 Hom.: 3

Mitomap

No disease associated.

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Oct 17, 2019

The NC_012920.1:m.8548T>C (YP_003024031.1:p.Ser8Pro) variant in MTATP6 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Benign	0.086
Hmtvar	Benign	0.33
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
DEOGEN2	Benign	0.060	T
LIST_S2	Benign	0.55	T
MutationTaster	Benign	1.0	N;D
PROVEAN	Benign	-1.3	N
Sift4G	Benign	0.10	T
GERP RS		0.29
Varity_R		0.26

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1603221580; hg19: chrM-8549;