2-27309900-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_002437.5(MPV17):c.*12T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000918 in 1,611,112 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (1 hom.)
• Consequence: MPV17 NM_002437.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.259

Genes affected

MPV17 (HGNC:7224): (mitochondrial inner membrane protein MPV17) This gene encodes a mitochondrial inner membrane protein that is implicated in the metabolism of reactive oxygen species. Mutations in this gene have been associated with the hepatocerebral form of mitochondrial DNA depletion syndrome (MDDS). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011353552).
• BP6: Variant 2-27309900-A-C is Benign according to our data. Variant chr2-27309900-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 387355.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17	NM_002437.5	c.*12T>G		3_prime_UTR_variant	8/8	ENST00000380044.6
MPV17	XM_005264326.5	c.*12T>G		3_prime_UTR_variant	8/8
MPV17	XM_017004151.2	c.*12T>G		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17	ENST00000380044.6	c.*12T>G		3_prime_UTR_variant	8/8	1	NM_002437.5	P1

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000916 AC: 230 AN: 251030 Hom.: 1 AF XY: 0.000958 AC XY: 130 AN XY: 135712

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000932 AC: 1360 AN: 1458794 Hom.: 1 Cov.: 29 AF XY: 0.000908 AC XY: 659 AN XY: 725976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000522

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000912

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74484

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000759

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000848 AC: 103

EpiCase AF: 0.00120

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	1.7
Dann	Benign	0.44
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.87	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.40
ClinPred		0.026	T
GERP RS		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs201202659; hg19: chr2-27532768;