rs754702528

Variant names:

• chr5-110739115-C-A
• rs754702528
• NM_138773.4:c.-5C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_138773.4(SLC25A46):​c.-5C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,545,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SLC25A46 NM_138773.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0600
• Publications: 0 publications found

Genes affected

SLC25A46 (HGNC:25198): (solute carrier family 25 member 46) This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]

TMEM232 (HGNC:37270): (transmembrane protein 232) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152176) while in subpopulation NFE AF = 0.000235 (16/68026). AF 95% confidence interval is 0.000147. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.-5C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_138773.4	c.-5C>A		5_prime_UTR_variant	Exon 1 of 8	ENST00000355943.8	NP_620128.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.-5C>A		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3
SLC25A46	ENST00000355943.8	c.-5C>A		5_prime_UTR_variant	Exon 1 of 8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000324 AC: 48 AN: 148024 AF XY: 0.000365

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00372

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000177

Gnomad OTH exome AF: 0.000468

GnomAD4 exome AF: 0.000244 AC: 340 AN: 1393818 Hom.: 1 Cov.: 31 AF XY: 0.000276 AC XY: 190 AN XY: 687568

African (AFR) AF: 0.0000635 AC: 2 AN: 31492

American (AMR) AF: 0.000168 AC: 6 AN: 35618

Ashkenazi Jewish (ASJ) AF: 0.00350 AC: 88 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 35692

South Asian (SAS) AF: 0.0000759 AC: 6 AN: 79102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46028

Middle Eastern (MID) AF: 0.00352 AC: 16 AN: 4546

European-Non Finnish (NFE) AF: 0.000185 AC: 199 AN: 1078426

Other (OTH) AF: 0.000398 AC: 23 AN: 57802

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000693 Hom.: 1

Bravo AF: 0.000253

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 08, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; Alters the Kozak sequence, which plays a major role in the initiation of translation -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		-0.060
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs754702528; hg19: chr5-110074816;