rs151055603

Positions:

• chr5-110743781-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138773.4(SLC25A46):​c.378A>G​(p.Gln126Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00532 in 1,605,066 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (33 hom.)
• Consequence: SLC25A46 NM_138773.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.351

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]

SLC25A46 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-110743781-A-G is Benign according to our data. Variant chr5-110743781-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 475793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-110743781-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.351 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00412 (627/152264) while in subpopulation NFE AF= 0.00563 (383/67972). AF 95% confidence interval is 0.00517. There are 3 homozygotes in gnomad4. There are 311 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC25A46	NM_138773.4	c.378A>G	p.Gln126Gln	synonymous_variant	3/8	ENST00000355943.8	NP_620128.1
SLC25A46	NM_001303249.3	c.378A>G	p.Gln126Gln	synonymous_variant	3/8		NP_001290178.1
SLC25A46	NM_001303250.3	c.105A>G	p.Gln35Gln	synonymous_variant	3/8		NP_001290179.1
SLC25A46	NR_138151.2	n.491A>G		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8	c.378A>G	p.Gln126Gln	synonymous_variant	3/8	1	NM_138773.4	ENSP00000348211.3

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152146 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00563

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00448 AC: 1112 AN: 248170 Hom.: 3 AF XY: 0.00486 AC XY: 652 AN XY: 134286

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.000220

Gnomad SAS exome AF: 0.00160

Gnomad FIN exome AF: 0.00825

Gnomad NFE exome AF: 0.00606

Gnomad OTH exome AF: 0.00397

GnomAD4 exome AF: 0.00544 AC: 7906 AN: 1452802 Hom.: 33 Cov.: 28 AF XY: 0.00520 AC XY: 3759 AN XY: 723012

Gnomad4 AFR exome AF: 0.000632

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00833

Gnomad4 NFE exome AF: 0.00602

Gnomad4 OTH exome AF: 0.00504

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152264 Hom.: 3 Cov.: 33 AF XY: 0.00418 AC XY: 311 AN XY: 74442

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00563

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00478 Hom.: 0

Bravo AF: 0.00400

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC25A46: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	- -

Neuropathy, hereditary motor and sensory, type 6B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.3
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151055603; hg19: chr5-110079482;