rs151055603

Variant names:

• chr5-110743781-A-G
• rs151055603
• NM_138773.4:c.378A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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]

SLC25A46 Gene-Disease associations (from GenCC):

• neuropathy, hereditary motor and sensory, type 6B

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• pontocerebellar hypoplasia, type 1E

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hereditary motor and sensory neuropathy type 6

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 475793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138773.4. 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
	SLC25A46	NM_138773.4	MANE Select	c.378A>G	p.Gln126Gln	synonymous	Exon 3 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.378A>G	p.Gln126Gln	synonymous	Exon 3 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.105A>G	p.Gln35Gln	synonymous	Exon 3 of 8	NP_001290179.1	B4DY98

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC25A46	ENST00000355943.8	TSL:1 MANE Select	c.378A>G	p.Gln126Gln	synonymous	Exon 3 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.378A>G	p.Gln126Gln	synonymous	Exon 3 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.378A>G	p.Gln126Gln	synonymous	Exon 3 of 8	ENSP00000399717.2	Q96AG3-3

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

GnomAD2 exomes AF: 0.00448 AC: 1112 AN: 248170 AF XY: 0.00486

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 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

African (AFR) AF: 0.000632 AC: 21 AN: 33234

American (AMR) AF: 0.00136 AC: 60 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 282 AN: 25898

East Asian (EAS) AF: 0.000152 AC: 6 AN: 39356

South Asian (SAS) AF: 0.00152 AC: 129 AN: 85132

European-Finnish (FIN) AF: 0.00833 AC: 443 AN: 53184

Middle Eastern (MID) AF: 0.000526 AC: 3 AN: 5706

European-Non Finnish (NFE) AF: 0.00602 AC: 6660 AN: 1106202

Other (OTH) AF: 0.00504 AC: 302 AN: 59934

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

African (AFR) AF: 0.000674 AC: 28 AN: 41572

American (AMR) AF: 0.00510 AC: 78 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 37 AN: 3466

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00800 AC: 85 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00563 AC: 383 AN: 67972

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00478 Hom.: 0

Bravo AF: 0.00400

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Neuropathy, hereditary motor and sensory, type 6B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.3
DANN	Benign	0.74
PhyloP100		-0.35
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=291/9	polymorphism

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

Other links and lift over

dbSNP: rs151055603; hg19: chr5-110079482;