chr4-185143605-GCGCCCGCC-G

Variant names:

• chr4-185143605-GCGCCCGCC-G
• rs143715129
• NM_001151.4:c.111+142_111+149delCCGCCCGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001151.4(SLC25A4):​c.111+142_111+149delCCGCCCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 148,378 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: SLC25A4 NM_001151.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 4 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00145 (204/140822) while in subpopulation AFR AF = 0.00495 (181/36548). AF 95% confidence interval is 0.00436. There are 2 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.111+142_111+149delCCGCCCGC		intron_variant	Intron 1 of 3	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.111+142_111+149delCCGCCCGC		intron_variant	Intron 1 of 3	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.111+142_111+149delCCGCCCGC		intron_variant	Intron 1 of 3	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 203 AN: 140726 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000343

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00104

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000184

Gnomad OTH AF: 0.000510

GnomAD4 exome AF: 0.000265 AC: 2 AN: 7556 Hom.: 0 AF XY: 0.000259 AC XY: 1 AN XY: 3854

African (AFR) AF: 0.00 AC: 0 AN: 202

American (AMR) AF: 0.00 AC: 0 AN: 40

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 72

East Asian (EAS) AF: 0.00 AC: 0 AN: 52

South Asian (SAS) AF: 0.00 AC: 0 AN: 230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 14

European-Non Finnish (NFE) AF: 0.000306 AC: 2 AN: 6532

Other (OTH) AF: 0.00 AC: 0 AN: 262

GnomAD4 genome AF: 0.00145 AC: 204 AN: 140822 Hom.: 2 Cov.: 0 AF XY: 0.00131 AC XY: 90 AN XY: 68546

African (AFR) AF: 0.00495 AC: 181 AN: 36548

American (AMR) AF: 0.000343 AC: 5 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.00105 AC: 5 AN: 4772

South Asian (SAS) AF: 0.00 AC: 0 AN: 4368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 262

European-Non Finnish (NFE) AF: 0.000184 AC: 12 AN: 65352

Other (OTH) AF: 0.000504 AC: 1 AN: 1984

Alfa AF: 0.00 Hom.: 816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143715129; hg19: chr4-186064759;