rs1232111681

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. 13/21 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
• 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 2 ACMG points.

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

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.208G>A	p.Val70Ile	missense	Exon 1 of 1	NP_001159349.1	Q7Z4Y8
	CYB5R3	NM_000398.7	MANE Select	c.22-3221G>A		intron	N/A	NP_000389.1	P00387-1
	CYB5R3	NM_001171660.2		c.121-3221G>A		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.208G>A	p.Val70Ile	missense	Exon 1 of 1	ENSP00000421076.1	Q7Z4Y8
	CYB5R3	ENST00000352397.10	TSL:1 MANE Select	c.22-3221G>A		intron	N/A	ENSP00000338461.6	P00387-1
	CYB5R3	ENST00000407332.6	TSL:1	c.22-3221G>A		intron	N/A	ENSP00000384457.2	A0A8J8Z3C6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251100 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.7
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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs1232111681; hg19: chr22-43036073;