4-185143605-GCGCCCGCCCGCCCGCC-GCGCCCGCCCGCC

Variant names:

• chr4-185143605-GCGCC-G
• rs143715129
• NM_001151.4:c.111+146_111+149delCCGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001151.4(SLC25A4):​c.111+146_111+149delCCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 7,544 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1644 hom., cov: 0)
  • Exomes 𝑓: 0.015 (7 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-GCGCC-G is Benign according to our data. Variant chr4-185143605-GCGCC-G is described in ClinVar as [Benign]. Clinvar id is 1177753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.015 (113/7544) while in subpopulation SAS AF = 0.0261 (6/230). AF 95% confidence interval is 0.0129. There are 7 homozygotes in GnomAdExome4. There are 54 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.111+146_111+149delCCGC		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+146_111+149delCCGC		intron_variant	Intron 1 of 3	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.111+146_111+149delCCGC		intron_variant	Intron 1 of 3	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 16961 AN: 140048 Hom.: 1639 Cov.: 0

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.0294

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.0776

Gnomad EAS AF: 0.0693

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.176

Gnomad NFE AF: 0.0763

Gnomad OTH AF: 0.129

GnomAD4 exome AF: 0.0150 AC: 113 AN: 7544 Hom.: 7 AF XY: 0.0140 AC XY: 54 AN XY: 3844

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

American (AMR) AF: 0.0250 AC: 1 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: 0.0261 AC: 6 AN: 230

European-Finnish (FIN) AF: 0.00658 AC: 1 AN: 152

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

European-Non Finnish (NFE) AF: 0.0153 AC: 100 AN: 6522

Other (OTH) AF: 0.0192 AC: 5 AN: 260

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.121 AC: 16985 AN: 140146 Hom.: 1644 Cov.: 0 AF XY: 0.119 AC XY: 8127 AN XY: 68232

African (AFR) AF: 0.251 AC: 9107 AN: 36264

American (AMR) AF: 0.0785 AC: 1139 AN: 14516

Ashkenazi Jewish (ASJ) AF: 0.0776 AC: 260 AN: 3352

East Asian (EAS) AF: 0.0695 AC: 330 AN: 4746

South Asian (SAS) AF: 0.132 AC: 570 AN: 4324

European-Finnish (FIN) AF: 0.0323 AC: 280 AN: 8678

Middle Eastern (MID) AF: 0.177 AC: 46 AN: 260

European-Non Finnish (NFE) AF: 0.0763 AC: 4973 AN: 65152

Other (OTH) AF: 0.129 AC: 254 AN: 1970

Alfa AF: 0.0283 Hom.: 816

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs143715129; hg19: chr4-186064759;