rs1057520206

Variant names:

• chrM-15848-A-G
• rs1057520206
• ENST00000361789.2:c.1102A>G

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16603354/MONDO:0044970/015

• 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
• Publications: 0 publications found

Genes affected

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]

TRNT (HGNC:7499): (mitochondrially encoded tRNA threonine)

TRNP (HGNC:7494): (mitochondrially encoded tRNA proline)

TRNP Gene-Disease associations (from GenCC):

• MERRF syndrome

  Inheritance: Mitochondrial Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

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

• BP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.1102A>G	p.Thr368Ala	missense_variant	Exon 1 of 1
TRNT	unassigned_transcript_4819	c.-40A>G		upstream_gene_variant
TRNP	unassigned_transcript_4820	c.*108T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.1102A>G	p.Thr368Ala	missense_variant	Exon 1 of 1	6		ENSP00000354554.2
MT-TT	ENST00000387460.2	n.-40A>G		upstream_gene_variant		6
MT-TP	ENST00000387461.2	n.*108T>C		downstream_gene_variant		6

Frequencies

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

Jul 10, 2023

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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

Jan 31, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leigh syndrome Benign:1

Oct 17, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-9.6
Mutation Taster		=95/5	polymorphism

Other links and lift over

dbSNP: rs1057520206; hg19: chrM-15849;