rs34486484

chr4-185145841-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001151.4(SLC25A4):c.681G>A(p.Val227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,218 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: SLC25A4 NM_001151.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.12

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-185145841-G-A is Benign according to our data. Variant chr4-185145841-G-A is described in ClinVar as [Benign]. Clinvar id is 139152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00897 (1366/152346) while in subpopulation AFR AF= 0.0305 (1267/41582). AF 95% confidence interval is 0.0291. There are 20 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A4	NM_001151.4	c.681G>A	p.Val227=	synonymous_variant	3/4	ENST00000281456.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A4	ENST00000281456.11	c.681G>A	p.Val227=	synonymous_variant	3/4	1	NM_001151.4	P1
SLC25A4	ENST00000491736.1	c.*458G>A		3_prime_UTR_variant, NMD_transcript_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.00896 AC: 1364 AN: 152228 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00270 AC: 680 AN: 251388 Hom.: 7 AF XY: 0.00195 AC XY: 265 AN XY: 135866

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00124 AC: 1813 AN: 1461872 Hom.: 24 Cov.: 32 AF XY: 0.00111 AC XY: 810 AN XY: 727234

Gnomad4 AFR exome AF: 0.0328

Gnomad4 AMR exome AF: 0.00197

Gnomad4 ASJ exome AF: 0.00566

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00897 AC: 1366 AN: 152346 Hom.: 20 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74488

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00444 Hom.: 5

Bravo AF: 0.0102

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2013	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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

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	-0.59
Cadd	Benign	10
Dann	Benign	0.51

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: rs34486484; hg19: chr4-186066995;