chr4-185143605-GCGCCCGCCCGCC-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001151.4(SLC25A4):​c.111+138_111+149delCCGCCCGCCCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 7,544 control chromosomes in the GnomAD database, including 610 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.47 (17045 hom., cov: 0)
  • Exomes 𝑓: 0.25 (610 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC25A4 NM_001151.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 4-185143605-GCGCCCGCCCGCC-G is Benign according to our data. Variant chr4-185143605-GCGCCCGCCCGCC-G is described in ClinVar as [Benign]. Clinvar id is 1276620.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.466 AC: 65605 AN: 140706 Hom.: 17023 Cov.: 0

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.681

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.628

Gnomad MID AF: 0.371

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.469

GnomAD4 exome AF: 0.245 AC: 1850 AN: 7544 Hom.: 610 AF XY: 0.277 AC XY: 1067 AN XY: 3850

African (AFR) AF: 0.0594 AC: 12 AN: 202

American (AMR) AF: 0.850 AC: 34 AN: 40

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 28 AN: 72

East Asian (EAS) AF: 0.712 AC: 37 AN: 52

South Asian (SAS) AF: 0.191 AC: 44 AN: 230

European-Finnish (FIN) AF: 0.882 AC: 134 AN: 152

Middle Eastern (MID) AF: 0.286 AC: 4 AN: 14

European-Non Finnish (NFE) AF: 0.227 AC: 1480 AN: 6520

Other (OTH) AF: 0.294 AC: 77 AN: 262

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.466 AC: 65652 AN: 140802 Hom.: 17045 Cov.: 0 AF XY: 0.470 AC XY: 32239 AN XY: 68532

African (AFR) AF: 0.217 AC: 7933 AN: 36546

American (AMR) AF: 0.546 AC: 7965 AN: 14580

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1635 AN: 3366

East Asian (EAS) AF: 0.681 AC: 3252 AN: 4772

South Asian (SAS) AF: 0.508 AC: 2221 AN: 4368

European-Finnish (FIN) AF: 0.628 AC: 5465 AN: 8700

Middle Eastern (MID) AF: 0.370 AC: 97 AN: 262

European-Non Finnish (NFE) AF: 0.544 AC: 35574 AN: 65340

Other (OTH) AF: 0.473 AC: 938 AN: 1984

Alfa AF: 0.410 Hom.: 816

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 18, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

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; COSMIC: COSV104385950;