7-103299440-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004279.3(PMPCB):c.241-3A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,567,602 control chromosomes in the GnomAD database, including 610 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 33)
  • Exomes 𝑓: 0.026 (561 hom.)
• Consequence: PMPCB NM_004279.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.1295
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.975

Genes affected

PMPCB (HGNC:9119): (peptidase, mitochondrial processing subunit beta) This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-103299440-A-G is Benign according to our data. Variant chr7-103299440-A-G is described in ClinVar as [Benign]. Clinvar id is 1280327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.021 (3195/152320) while in subpopulation NFE AF= 0.0294 (2001/68030). AF 95% confidence interval is 0.0283. There are 49 homozygotes in gnomad4. There are 1609 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 50 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMPCB	NM_004279.3	c.241-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000249269.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMPCB	ENST00000249269.9	c.241-3A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004279.3	P1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3197 AN: 152202 Hom.: 50 Cov.: 33

Gnomad AFR AF: 0.00458

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0262

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.0219 AC: 5392 AN: 246254 Hom.: 105 AF XY: 0.0227 AC XY: 3027 AN XY: 133084

Gnomad AFR exome AF: 0.00427

Gnomad AMR exome AF: 0.00732

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.0508

Gnomad NFE exome AF: 0.0271

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0259 AC: 36648 AN: 1415282 Hom.: 561 Cov.: 25 AF XY: 0.0258 AC XY: 18203 AN XY: 706670

Gnomad4 AFR exome AF: 0.00384

Gnomad4 AMR exome AF: 0.00833

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.0468

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0217

GnomAD4 genome AF: 0.0210 AC: 3195 AN: 152320 Hom.: 49 Cov.: 33 AF XY: 0.0216 AC XY: 1609 AN XY: 74470

Gnomad4 AFR AF: 0.00457

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.0262

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0526

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.0252 Hom.: 31

Bravo AF: 0.0173

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0248

EpiControl AF: 0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	7.5
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.040		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: rs79606522; hg19: chr7-102939887;