4-185143348-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001151.4(SLC25A4):c.-25G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,401,616 control chromosomes in the GnomAD database, including 1,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (284 hom., cov: 31)
  • Exomes 𝑓: 0.023 (871 hom.)
• Consequence: SLC25A4 NM_001151.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.82

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-185143348-G-A is Benign according to our data. Variant chr4-185143348-G-A is described in ClinVar as [Benign]. Clinvar id is 139153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A4	NM_001151.4	c.-25G>A		5_prime_UTR_variant	1/4	ENST00000281456.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A4	ENST00000281456.11	c.-25G>A		5_prime_UTR_variant	1/4	1	NM_001151.4	P1
SLC25A4	ENST00000491736.1	c.-25G>A		5_prime_UTR_variant, NMD_transcript_variant	1/4	5

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7342 AN: 151936 Hom.: 283 Cov.: 31

Gnomad AFR AF: 0.0981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0987

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0483 AC: 6871 AN: 142128 Hom.: 307 AF XY: 0.0456 AC XY: 3442 AN XY: 75492

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.0967

Gnomad ASJ exome AF: 0.0239

Gnomad EAS exome AF: 0.0883

Gnomad SAS exome AF: 0.0706

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0225 AC: 28159 AN: 1249574 Hom.: 871 Cov.: 17 AF XY: 0.0236 AC XY: 14678 AN XY: 622610

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0882

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0742

Gnomad4 FIN exome AF: 0.0501

Gnomad4 NFE exome AF: 0.00925

Gnomad4 OTH exome AF: 0.0293

GnomAD4 genome AF: 0.0484 AC: 7363 AN: 152042 Hom.: 284 Cov.: 31 AF XY: 0.0515 AC XY: 3830 AN XY: 74340

Gnomad4 AFR AF: 0.0984

Gnomad4 AMR AF: 0.0532

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0988

Gnomad4 SAS AF: 0.0803

Gnomad4 FIN AF: 0.0574

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0381 Hom.: 63

Bravo AF: 0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 01, 2011

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	12
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3733652; hg19: chr4-186064502;