22-42640067-C-T

Variant names:

• chr22-42640067-C-T
• rs1232111681
• NM_001165877.1:c.208G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001165877.1(ATP5MGL):​c.208G>A​(p.Val70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATP5MGL NM_001165877.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MGL	NM_001165877.1	c.208G>A	p.Val70Ile	missense_variant	Exon 1 of 1	ENST00000505920.1	NP_001159349.1
CYB5R3	NM_000398.7	c.22-3221G>A		intron_variant	Intron 1 of 8	ENST00000352397.10	NP_000389.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5MGL	ENST00000505920.1	c.208G>A	p.Val70Ile	missense_variant	Exon 1 of 1	6	NM_001165877.1	ENSP00000421076.1
CYB5R3	ENST00000352397.10	c.22-3221G>A		intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251100 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461542 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.208G>A (p.V70I) alteration is located in exon 1 (coding exon 1) of the ATP5L2 gene. This alteration results from a G to A substitution at nucleotide position 208, causing the valine (V) at amino acid position 70 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.51	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.066	T
Vest4		0.15
MutPred		0.80		Loss of sheet (P = 0.0817);
MVP		0.21
MPC		0.011
ClinPred		0.45	T
GERP RS		1.2
Varity_R		0.30
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs1232111681; hg19: chr22-43036073;