4-185143605-GCGCCCGCCCGCCCGCC-GCGCCCGCCCGCCCGCCCGCCCGCC

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001151.4(SLC25A4):​c.111+142_111+149dupCCGCCCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC25A4 NM_001151.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.378
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (153/140806) while in subpopulation NFE AF = 0.00197 (129/65338). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 75 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 154 AN: 140710 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000274

Gnomad AMI AF: 0.00452

Gnomad AMR AF: 0.000206

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.000115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.000510

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 7556 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 AN: 6532

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

GnomAD4 genome AF: 0.00109 AC: 153 AN: 140806 Hom.: 0 Cov.: 0 AF XY: 0.00109 AC XY: 75 AN XY: 68540

African (AFR) AF: 0.000274 AC: 10 AN: 36548

American (AMR) AF: 0.000206 AC: 3 AN: 14582

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4772

South Asian (SAS) AF: 0.00114 AC: 5 AN: 4368

European-Finnish (FIN) AF: 0.000115 AC: 1 AN: 8702

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

European-Non Finnish (NFE) AF: 0.00197 AC: 129 AN: 65338

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

Alfa AF: 0.000155 Hom.: 816

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.38

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;