4-185143289-C-A

Position:

• chr4-185143289-C-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.-84C>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 0.00801 in 749,178 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (73 hom.)
• Consequence: SLC25A4 NM_001151.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.303

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=-0.69).
• BP6: Variant 4-185143289-C-A is Benign according to our data. Variant chr4-185143289-C-A is described in ClinVar as [Benign]. Clinvar id is 348243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.-84C>A		5_prime_UTR_variant	1/4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.-84C>A		5_prime_UTR_variant	1/4	1	NM_001151.4	ENSP00000281456	P1
SLC25A4	ENST00000491736.1	c.-84C>A		5_prime_UTR_variant, NMD_transcript_variant	1/4	5		ENSP00000476711

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2943 AN: 151818 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00643

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00717

GnomAD4 exome AF: 0.00511 AC: 3050 AN: 597252 Hom.: 73 Cov.: 8 AF XY: 0.00526 AC XY: 1679 AN XY: 319172

Gnomad4 AFR exome AF: 0.0684

Gnomad4 AMR exome AF: 0.00319

Gnomad4 ASJ exome AF: 0.000779

Gnomad4 EAS exome AF: 0.0374

Gnomad4 SAS exome AF: 0.0145

Gnomad4 FIN exome AF: 0.000157

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.00823

GnomAD4 genome AF: 0.0194 AC: 2948 AN: 151926 Hom.: 94 Cov.: 32 AF XY: 0.0194 AC XY: 1440 AN XY: 74260

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.00642

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0304

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000324

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.0213

Asia WGS AF: 0.0230 AC: 81 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.69
CADD	Benign	12
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs183128370; hg19: chr4-186064443;