5-110739114-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_138773.4(SLC25A46):c.-6G>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 0.000241 in 1,545,618 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: SLC25A46 NM_138773.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.733

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 5-110739114-G-A is Benign according to our data. Variant chr5-110739114-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3043548.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.-6G>A		5_prime_UTR_variant	1/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.-6G>A		5_prime_UTR_variant	1/8
SLC25A46	NM_001303250.3	c.10+867G>A		intron_variant
SLC25A46	NR_138151.2	n.108G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.-6G>A		5_prime_UTR_variant	1/8	1	NM_138773.4	P1
SLC25A46	ENST00000447245.6	c.-6G>A		5_prime_UTR_variant	1/8	2
SLC25A46	ENST00000513807.5	c.-204+867G>A		intron_variant		2
SLC25A46	ENST00000508781.5	n.112+867G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152148 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

GnomAD3 exomes AF: 0.000332 AC: 49 AN: 147672 Hom.: 1 AF XY: 0.000366 AC XY: 29 AN XY: 79202

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 SAS exome AF: 0.0000881

Gnomad FIN exome AF: 0.0000754

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000469

GnomAD4 exome AF: 0.000245 AC: 341 AN: 1393470 Hom.: 1 Cov.: 31 AF XY: 0.000276 AC XY: 190 AN XY: 687400

Gnomad4 AFR exome AF: 0.0000635

Gnomad4 AMR exome AF: 0.000169

Gnomad4 ASJ exome AF: 0.00350

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000759

Gnomad4 FIN exome AF: 0.0000218

Gnomad4 NFE exome AF: 0.000185

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74328

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000716 Hom.: 1

Bravo AF: 0.000253

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLC25A46-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	12
Dann	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs753376360; hg19: chr5-110074815;