4-185143289-C-A

Variant names:

• chr4-185143289-C-A
• rs183128370
• NM_001151.4:c.-84C>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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]

SLC25A4 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• mitochondrial DNA depletion syndrome 12B (cardiomyopathic type), autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• Fontaine progeroid syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P
• mitochondrial DNA depletion syndrome 12A (cardiomyopathic type), autosomal dominant

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sengers syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.-84C>A		5_prime_UTR_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.-84C>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.-84C>A		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000476711.1
SLC25A4	ENST00000491736.1	n.-84C>A		5_prime_UTR_variant	Exon 1 of 4	5		ENSP00000476711.1

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

African (AFR) AF: 0.0684 AC: 857 AN: 12538

American (AMR) AF: 0.00319 AC: 92 AN: 28874

Ashkenazi Jewish (ASJ) AF: 0.000779 AC: 13 AN: 16680

East Asian (EAS) AF: 0.0374 AC: 898 AN: 24018

South Asian (SAS) AF: 0.0145 AC: 859 AN: 59174

European-Finnish (FIN) AF: 0.000157 AC: 7 AN: 44492

Middle Eastern (MID) AF: 0.00574 AC: 19 AN: 3312

European-Non Finnish (NFE) AF: 0.000182 AC: 69 AN: 379472

Other (OTH) AF: 0.00823 AC: 236 AN: 28692

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

African (AFR) AF: 0.0624 AC: 2590 AN: 41490

American (AMR) AF: 0.00642 AC: 98 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0304 AC: 155 AN: 5102

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4818

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10560

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67904

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00299 Hom.: 2

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

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.30
PromoterAI		0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs183128370; hg19: chr4-186064443;