chr4-185143605-G-GCGCCCGCCCGCC

Variant names:

• chr4-185143605-G-GCGCCCGCCCGCC
• rs143715129
• NM_001151.4:c.111+138_111+149dupCCGCCCGCCCGC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001151.4(SLC25A4):​c.111+138_111+149dupCCGCCCGCCCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000050 (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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.111+138_111+149dupCCGCCCGCCCGC		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+138_111+149dupCCGCCCGCCCGC		intron_variant	Intron 1 of 3	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.111+138_111+149dupCCGCCCGCCCGC		intron_variant	Intron 1 of 3	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes AF: 0.0000497 AC: 7 AN: 140724 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

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: 0.0000497 AC: 7 AN: 140820 Hom.: 0 Cov.: 0 AF XY: 0.0000729 AC XY: 5 AN XY: 68546

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 36548

American (AMR) AF: 0.0000686 AC: 1 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: 0.00137 AC: 6 AN: 4366

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: 0.00 AC: 0 AN: 65352

Other (OTH) AF: 0.00 AC: 0 AN: 1984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000004), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 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;