rs201202659

Variant names:

• chr2-27309900-A-C
• rs201202659
• NM_002437.5:c.*12T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. 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
• Publications: 1 publications found

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]

MPV17 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 6 (hepatocerebral type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• Charcot-Marie-Tooth disease, axonal, type 2EE

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• 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 VariationId is 387355.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002437.5. 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
	MPV17	NM_002437.5	MANE Select	c.*12T>G		3_prime_UTR	Exon 8 of 8	NP_002428.1	P39210

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPV17	ENST00000380044.6	TSL:1 MANE Select	c.*12T>G		3_prime_UTR	Exon 8 of 8	ENSP00000369383.1	P39210
	MPV17	ENST00000233545.6	TSL:1	c.*12T>G		3_prime_UTR	Exon 7 of 7	ENSP00000233545.2	P39210
	MPV17	ENST00000402310.5	TSL:5	c.490T>G	p.Ser164Ala	missense	Exon 7 of 7	ENSP00000383955.1	B5MC53

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

GnomAD2 exomes AF: 0.000916 AC: 230 AN: 251030 AF XY: 0.000958

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.000850 AC: 38 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86134

European-Finnish (FIN) AF: 0.000487 AC: 26 AN: 53418

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00101 AC: 1118 AN: 1109250

Other (OTH) AF: 0.000912 AC: 55 AN: 60316

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

African (AFR) AF: 0.0000722 AC: 3 AN: 41578

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000890 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Mitochondrial DNA depletion syndrome 6 (hepatocerebral type) (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
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
PhyloP100		-0.26
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
Mutation Taster		=99/1	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: rs201202659; hg19: chr2-27532768;