rs202123515

Variant names:

• chr5-110746300-C-A
• rs202123515
• NM_138773.4:c.416C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-110746300-C-A
• chr5-110746300-C-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_138773.4(SLC25A46):​c.416C>A​(p.Thr139Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000879 in 1,589,750 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00092 (8 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 7.14
• Publications: 1 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_138773.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.026061535).
• BP6: Variant 5-110746300-C-A is Benign according to our data. Variant chr5-110746300-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475795.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000473 (72/152296) while in subpopulation SAS AF = 0.0029 (14/4822). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.416C>A	p.Thr139Asn	missense	Exon 4 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.416C>A	p.Thr139Asn	missense	Exon 4 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.143C>A	p.Thr48Asn	missense	Exon 4 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.416C>A	p.Thr139Asn	missense	Exon 4 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.416C>A	p.Thr139Asn	missense	Exon 4 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.416C>A	p.Thr139Asn	missense	Exon 4 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes AF: 0.000467 AC: 71 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000843 AC: 191 AN: 226474 AF XY: 0.00110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000210

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.000682

Gnomad OTH exome AF: 0.00128

GnomAD4 exome AF: 0.000922 AC: 1325 AN: 1437454 Hom.: 8 Cov.: 28 AF XY: 0.00109 AC XY: 783 AN XY: 715154

African (AFR) AF: 0.0000969 AC: 3 AN: 30946

American (AMR) AF: 0.000180 AC: 7 AN: 38784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.0000526 AC: 2 AN: 37992

South Asian (SAS) AF: 0.00454 AC: 372 AN: 81850

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53216

Middle Eastern (MID) AF: 0.00508 AC: 29 AN: 5706

European-Non Finnish (NFE) AF: 0.000755 AC: 834 AN: 1103972

Other (OTH) AF: 0.00128 AC: 76 AN: 59442

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34 AN XY: 74470

African (AFR) AF: 0.0000722 AC: 3 AN: 41554

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000560 Hom.: 3

Bravo AF: 0.000431

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuropathy, hereditary motor and sensory, type 6B (1)
-	-	1	SLC25A46-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.36
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Polyphen		0.93	P
Vest4		0.65
MVP		0.72
MPC		0.18
ClinPred		0.054	T
GERP RS		4.8
Varity_R		0.21
gMVP		0.68
Mutation Taster		=93/7	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: rs202123515; hg19: chr5-110082001;