5-110739267-C-A

Variant names:

• chr5-110739267-C-A
• rs147648476
• NM_138773.4:c.148C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_138773.4(SLC25A46):​c.148C>A​(p.Pro50Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000548 in 1,580,704 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (3 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7 O:1
• Conservation: PhyloP100: 6.52
• 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000525 (80/152350) while in subpopulation AMR AF = 0.00157 (24/15310). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 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.148C>A	p.Pro50Thr	missense	Exon 1 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.10+1020C>A		intron	N/A	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.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.148C>A	p.Pro50Thr	missense	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

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: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000256 AC: 49 AN: 191398 AF XY: 0.000242

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000678

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.000604

GnomAD4 exome AF: 0.000551 AC: 787 AN: 1428354 Hom.: 3 Cov.: 31 AF XY: 0.000506 AC XY: 358 AN XY: 707296

African (AFR) AF: 0.0000606 AC: 2 AN: 33014

American (AMR) AF: 0.000432 AC: 17 AN: 39356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25448

East Asian (EAS) AF: 0.00 AC: 0 AN: 38222

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81634

European-Finnish (FIN) AF: 0.0000401 AC: 2 AN: 49830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.000656 AC: 719 AN: 1095972

Other (OTH) AF: 0.000778 AC: 46 AN: 59144

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74504

African (AFR) AF: 0.000144 AC: 6 AN: 41586

American (AMR) AF: 0.00157 AC: 24 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000747 Hom.: 0

Bravo AF: 0.000737

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000117 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	Neuropathy, hereditary motor and sensory, type 6B (1)
-	1	-	not specified (1)
-	-	-	Neuropathy, hereditary motor and sensory, type 6B;C5543328:Pontocerebellar hypoplasia, type 1E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.66
MVP		0.82
MPC		0.38
ClinPred		0.72	D
GERP RS		5.1
PromoterAI		-0.012	Neutral
Varity_R		0.67
gMVP		0.68
Mutation Taster		=14/86	disease causing

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: rs147648476; hg19: chr5-110074968; COSMIC: COSV63507328; COSMIC: COSV63507328;