rs1057520206

chrM-15848-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BP6_Strong BS2

The ENST00000361789.2(MT-CYB):c.1102A>G(p.Thr368Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T368I) has been classified as Likely benign.

• Frequency: Mitomap GenBank: 𝑓 0.00060 (AC: 38)
• Consequence: MT-CYB ENST00000361789.2 missense
• Scores: Apogee2 Benign 0.0087
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 No linked disesase in Mitomap
• Conservation: PhyloP100: -9.61

Genes affected

CYTB (HGNC:):

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-TT (HGNC:7499): (mitochondrially encoded tRNA threonine)

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Apogee2 supports a benign effect, 0.00871535 < 0.5 .
• BP6: Variant M-15848-A-G is Benign according to our data. Variant chrM-15848-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 377369.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomadMitoHomoplasmic at 217

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYTB	CYTB.1	c.1102A>G	p.Thr368Ala	missense_variant	1/1
TRNT	TRNT.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-CYB	ENST00000361789.2	c.1102A>G	p.Thr368Ala	missense_variant	1/1			P1
MT-TT	ENST00000387460.2			upstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

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

Mitomap GenBank AF: 0.00060 AC: 38

Gnomad homoplasmic AF: 0.0038 AC: 217 AN: 56429

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56429

Alfa AF: 0.000891 Hom.: 4

Mitomap

No disease associated.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Jul 10, 2023

The m.15848A>G (p.T368A) variant in MT-CYB was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel on July 10, 2023. There are no individuals or families with primary mitochondrial disease with this variant reported in the medical literature to our knowledge. This variant is present at varying frequencies in population databases. The frequency in the MITOMAP GenBank sequences in 38/59,389 (0.064%) spread over 13 top level (single letter) haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences of this variant in the Helix dataset in 98/195,983 (0.050%), in addition to 10 heteroplasmic occurrences, spread over 15 top level haplogroups with European, Asian, and African ancestry. The frequency of homoplasmic occurrences in gnomAD v3.1.2 is 217/56,429 (0.385%) in addition to two heteroplasmic occurrences, spread over 13 top level haplogroups with European, Asian, and African ancestry. The overall frequency is notably higher in this database than in MITOMAP and Helix, with 185 of the gnomAD sequences categorized as Latin American and all in top level haplogroup A. Therefore, the frequency of this variant meets neither criteria for pathogenicity (<0.002%) nor benign status (>0.5%). The computational predictor APOGEE gives scores of 0.33 (“neutral”) in APOGEE1 and 0.0087 (“benign”) in APOGEE2 (Min=0, Max=1), predicting no impact on gene function (BP4). There are no cybrids, single fiber studies, or other functional assays reported for this variant to date. In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 10, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied: BP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jan 31, 2017

- -

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.15848A>G (YP_003024038.1:p.Thr368Ala) variant in MTCYB 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	0.0087
Hmtvar	Benign	0.090
AlphaMissense	Benign	0.061

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057520206; hg19: chrM-15849;