chr19-18193394-C-A

Position:

• chr19-18193394-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032683.3(MPV17L2):​c.113C>A​(p.Ala38Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000706 in 1,415,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MPV17L2 NM_032683.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61

Genes affected

MPV17L2 (HGNC:28177): (MPV17 mitochondrial inner membrane protein like 2) Involved in mitochondrial ribosome assembly and positive regulation of mitochondrial translation. Located in mitochondrial inner membrane. Part of mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MPV17L2	NM_032683.3	c.113C>A	p.Ala38Glu	missense_variant	1/5	ENST00000599612.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MPV17L2	ENST00000599612.3	c.113C>A	p.Ala38Glu	missense_variant	1/5	1	NM_032683.3	P1
MPV17L2	ENST00000532896.5	n.163C>A		non_coding_transcript_exon_variant	1/3	2
MPV17L2	ENST00000533807.3	n.145C>A		non_coding_transcript_exon_variant	1/4	2
MPV17L2	ENST00000534421.1	n.177C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.06e-7 AC: 1 AN: 1415976 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 702584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The c.113C>A (p.A38E) alteration is located in exon 1 (coding exon 1) of the MPV17L2 gene. This alteration results from a C to A substitution at nucleotide position 113, causing the alanine (A) at amino acid position 38 to be replaced by a glutamic acid (E). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	0.93	D;D
PrimateAI	Pathogenic	0.85	D
Sift4G	Uncertain	0.021	D
Polyphen		0.98	D
Vest4		0.76
MutPred		0.75		Loss of MoRF binding (P = 0.112);
MVP		0.62
MPC		1.4
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Varity_R		0.48
gMVP		0.92

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: rs1478146134; hg19: chr19-18304204;