NM_001151.4:c.-25G>A

Variant names:

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

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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001151.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A4	NM_001151.4	MANE Select	c.-25G>A		5_prime_UTR	Exon 1 of 4	NP_001142.2	A0A0S2Z3H3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A4	ENST00000281456.11	TSL:1 MANE Select	c.-25G>A		5_prime_UTR	Exon 1 of 4	ENSP00000281456.5	P12235
	SLC25A4	ENST00000948444.1		c.-25G>A		5_prime_UTR	Exon 1 of 4	ENSP00000618503.1
	SLC25A4	ENST00000948442.1		c.-25G>A		5_prime_UTR	Exon 1 of 4	ENSP00000618501.1

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 (1)

Computational scores

Source: dbNSFP v4.9

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;