22-42640104-GAC-TAG

Variant names:

• chr22-42640104-GAC-TAG
• NM_001165877.1:c.169_171delGTCinsCTA
• ATP5MGL p.Val57Leu

Variant summary

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

The NM_001165877.1(ATP5MGL):​c.169_171delGTCinsCTA​(p.Val57Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V57F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATP5MGL NM_001165877.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.41
• Publications: 0 publications found

Genes affected

ATP5MGL (HGNC:13213): (ATP synthase membrane subunit g like) Predicted to enable proton transmembrane transporter activity. Predicted to be involved in ATP synthesis coupled proton transport. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

CYB5R3 Gene-Disease associations (from GenCC):

• methemoglobinemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• methemoglobinemia due to deficiency of methemoglobin reductase

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hereditary methemoglobinemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165877.1. 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
	ATP5MGL	NM_001165877.1	MANE Select	c.169_171delGTCinsCTA	p.Val57Leu	missense	N/A	NP_001159349.1	Q7Z4Y8
	CYB5R3	NM_000398.7	MANE Select	c.22-3260_22-3258delGTCinsCTA		intron	N/A	NP_000389.1	P00387-1
	CYB5R3	NM_001171660.2		c.121-3260_121-3258delGTCinsCTA		intron	N/A	NP_001165131.1	P00387-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5MGL	ENST00000505920.1	TSL:6 MANE Select	c.169_171delGTCinsCTA	p.Val57Leu	missense	N/A	ENSP00000421076.1	Q7Z4Y8
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.22-3260_22-3258delGTCinsCTA		intron	N/A	ENSP00000338461.6	P00387-1
	CYB5R3	ENST00000407332.6	TSL:1	c.22-3260_22-3258delGTCinsCTA		intron	N/A	ENSP00000384457.2	A0A8J8Z3C6

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.4

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-43036110;