rs3733652

Variant names:

• chr4-185143348-G-A
• rs3733652
• NM_001151.4:c.-25G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-185143348-G-A
• chr4-185143348-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001151.4(SLC25A4):​c.-25G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,401,616 control chromosomes in the GnomAD database, including 1,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (284 hom., cov: 31)
  • Exomes 𝑓: 0.023 (871 hom.)
• Consequence: SLC25A4 NM_001151.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.82
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-185143348-G-A is Benign according to our data. Variant chr4-185143348-G-A is described in ClinVar as [Benign]. Clinvar id is 139153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.-25G>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.-25G>A		5_prime_UTR_variant	Exon 1 of 4	1	NM_001151.4	ENSP00000281456.5
SLC25A4	ENST00000491736.1	n.-25G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000476711.1
SLC25A4	ENST00000491736.1	n.-25G>A		5_prime_UTR_variant	Exon 1 of 4	5		ENSP00000476711.1

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7342 AN: 151936 Hom.: 283 Cov.: 31

Gnomad AFR AF: 0.0981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0987

Gnomad SAS AF: 0.0804

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0483 AC: 6871 AN: 142128 AF XY: 0.0456

Gnomad AFR exome AF: 0.0937

Gnomad AMR exome AF: 0.0967

Gnomad ASJ exome AF: 0.0239

Gnomad EAS exome AF: 0.0883

Gnomad FIN exome AF: 0.0538

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0330

GnomAD4 exome AF: 0.0225 AC: 28159 AN: 1249574 Hom.: 871 Cov.: 17 AF XY: 0.0236 AC XY: 14678 AN XY: 622610

African (AFR) AF: 0.103 AC: 2768 AN: 26926

American (AMR) AF: 0.0882 AC: 2957 AN: 33534

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 538 AN: 23286

East Asian (EAS) AF: 0.106 AC: 3473 AN: 32672

South Asian (SAS) AF: 0.0742 AC: 5543 AN: 74656

European-Finnish (FIN) AF: 0.0501 AC: 2395 AN: 47800

Middle Eastern (MID) AF: 0.0265 AC: 140 AN: 5274

European-Non Finnish (NFE) AF: 0.00925 AC: 8814 AN: 953234

Other (OTH) AF: 0.0293 AC: 1531 AN: 52192

GnomAD4 genome AF: 0.0484 AC: 7363 AN: 152042 Hom.: 284 Cov.: 31 AF XY: 0.0515 AC XY: 3830 AN XY: 74340

African (AFR) AF: 0.0984 AC: 4087 AN: 41524

American (AMR) AF: 0.0532 AC: 813 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.0988 AC: 506 AN: 5122

South Asian (SAS) AF: 0.0803 AC: 388 AN: 4834

European-Finnish (FIN) AF: 0.0574 AC: 606 AN: 10566

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0117 AC: 796 AN: 67930

Other (OTH) AF: 0.0403 AC: 85 AN: 2110

Alfa AF: 0.0404 Hom.: 79

Bravo AF: 0.0510

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 01, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.84
PhyloP100		1.8
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs3733652; hg19: chr4-186064502;