NM_001165877.1:c.101C>G

Variant names:

• chr22-42640174-G-C
• NM_001165877.1:c.101C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001165877.1(ATP5MGL):​c.101C>G​(p.Thr34Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP5MGL NM_001165877.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.77

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14369428).
• BP6: Variant 22-42640174-G-C is Benign according to our data. Variant chr22-42640174-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3458020.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5MGL	NM_001165877.1	c.101C>G	p.Thr34Ser	missense_variant	Exon 1 of 1	ENST00000505920.1	NP_001159349.1
CYB5R3	NM_000398.7	c.22-3328C>G		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.101C>G	p.Thr34Ser	missense_variant	Exon 1 of 1	6	NM_001165877.1	ENSP00000421076.1
CYB5R3	ENST00000352397.10	c.22-3328C>G		intron_variant	Intron 1 of 8	1	NM_000398.7	ENSP00000338461.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 03, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.15
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Vest4		0.11
MutPred		0.59		Gain of relative solvent accessibility (P = 0.0215);
MVP		0.33
MPC		0.0077
ClinPred		0.21	T
GERP RS		-0.016
Varity_R		0.056
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-43036180;