NM_001151.4:c.46_47delGG

Variant names:

• chr4-185143414-CGG-C
• NM_001151.4:c.46_47delGG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001151.4(SLC25A4):​c.46_47delGG​(p.Gly16ArgfsTer32) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC25A4 NM_001151.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

Genes affected

SLC25A4 (HGNC:10990): (solute carrier family 25 member 4) This gene is a member of the mitochondrial carrier subfamily of solute carrier protein genes. The product of this gene functions as a gated pore that translocates ADP from the cytoplasm into the mitochondrial matrix and ATP from the mitochondrial matrix into the cytoplasm. The protein forms a homodimer embedded in the inner mitochondria membrane. Mutations in this gene have been shown to result in autosomal dominant progressive external opthalmoplegia and familial hypertrophic cardiomyopathy. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.949 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-185143414-CGG-C is Pathogenic according to our data. Variant chr4-185143414-CGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3572858.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.46_47delGG	p.Gly16ArgfsTer32	frameshift_variant	Exon 1 of 4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.46_47delGG	p.Gly16ArgfsTer32	frameshift_variant	Exon 1 of 4	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.46_47delGG		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive Pathogenic:1

Dec 19, 2022

Clinical Genomics Laboratory, Stanford Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly16Argfs*32 variant in the SLC25A4 gene has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant results in a 2 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 32 amino acids downstream. Loss of function is an established mechanism of disease for the SLC25A4 gene. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Gly16Argfs*32 variant as likely pathogenic for mitochondrial DNA depletion syndrome in an autosomal recessive manner based on the information above. [ACMG evidence codes used: PVS1; PM2] -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-186064568;