rs143511445

Positions:

• chr4-185145142-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS1

The ENST00000281456.11(SLC25A4):​c.490A>G​(p.Ile164Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000298 in 1,612,952 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: SLC25A4 ENST00000281456.11 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 7.46

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM1: In a chain ADP/ATP translocase 1 (size 296) in uniprot entity ADT1_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in ENST00000281456.11
• BP4: Computational evidence support a benign effect (MetaRNN=0.01031971).
• BP6: Variant 4-185145142-A-G is Benign according to our data. Variant chr4-185145142-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 215168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00157 (239/152234) while in subpopulation AFR AF= 0.00554 (230/41524). AF 95% confidence interval is 0.00495. There are 1 homozygotes in gnomad4. There are 115 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A4	NM_001151.4	c.490A>G	p.Ile164Val	missense_variant	2/4	ENST00000281456.11	NP_001142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A4	ENST00000281456.11	c.490A>G	p.Ile164Val	missense_variant	2/4	1	NM_001151.4	ENSP00000281456	P1
SLC25A4	ENST00000491736.1	c.490A>G	p.Ile164Val	missense_variant, NMD_transcript_variant	2/4	5		ENSP00000476711

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000379 AC: 95 AN: 250426 Hom.: 0 AF XY: 0.000273 AC XY: 37 AN XY: 135338

Gnomad AFR exome AF: 0.00519

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1460718 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 98 AN XY: 726478

Gnomad4 AFR exome AF: 0.00613

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74434

Gnomad4 AFR AF: 0.00554

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.00184

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000420 AC: 51

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SLC25A4 p.Ile164Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs143511445) and ClinVar (classified as likely benign by GeneDx and benign by Athena Diagnostics Inc). The variant was identified in control databases in 146 of 281816 chromosomes at a frequency of 0.000518 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 135 of 24898 chromosomes (freq: 0.005422), Other in 3 of 7190 chromosomes (freq: 0.000417) and Latino in 8 of 35326 chromosomes (freq: 0.000227), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), and South Asian populations. The p.Ile164 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing, however this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 16, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.38
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Polyphen		0.010	B
Vest4		0.34
MVP		0.79
MPC		1.5
ClinPred		0.040	T
GERP RS		5.5
Varity_R		0.32
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143511445; hg19: chr4-186066296;