rs200566665

Variant names:

• chr5-110739354-G-A
• rs200566665
• NM_138773.4:c.235G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-110739354-G-A
• chr5-110739354-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138773.4(SLC25A46):​c.235G>A​(p.Glu79Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00198 in 1,561,996 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E79Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (9 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 5.64
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008162528).
• BP6: Variant 5-110739354-G-A is Benign according to our data. Variant chr5-110739354-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 542455.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00141 (214/152034) while in subpopulation NFE AF = 0.00256 (174/67940). AF 95% confidence interval is 0.00225. There are 1 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.235G>A	p.Glu79Lys	missense	Exon 1 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.235G>A	p.Glu79Lys	missense	Exon 1 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.10+1107G>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.235G>A	p.Glu79Lys	missense	Exon 1 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000923605.1		c.235G>A	p.Glu79Lys	missense	Exon 1 of 8	ENSP00000593664.1
	SLC25A46	ENST00000447245.6	TSL:2	c.235G>A	p.Glu79Lys	missense	Exon 1 of 8	ENSP00000399717.2	Q96AG3-3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 151912 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00136 AC: 227 AN: 167026 AF XY: 0.00120

Gnomad AFR exome AF: 0.000513

Gnomad AMR exome AF: 0.000533

Gnomad ASJ exome AF: 0.00174

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00129

GnomAD4 exome AF: 0.00204 AC: 2881 AN: 1409962 Hom.: 9 Cov.: 31 AF XY: 0.00204 AC XY: 1421 AN XY: 697136

African (AFR) AF: 0.000492 AC: 16 AN: 32536

American (AMR) AF: 0.000561 AC: 21 AN: 37450

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 64 AN: 25284

East Asian (EAS) AF: 0.00 AC: 0 AN: 37300

South Asian (SAS) AF: 0.000323 AC: 26 AN: 80492

European-Finnish (FIN) AF: 0.000265 AC: 12 AN: 45352

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5718

European-Non Finnish (NFE) AF: 0.00244 AC: 2649 AN: 1087218

Other (OTH) AF: 0.00157 AC: 92 AN: 58612

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152034 Hom.: 1 Cov.: 33 AF XY: 0.00124 AC XY: 92 AN XY: 74338

African (AFR) AF: 0.000434 AC: 18 AN: 41498

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 67940

Other (OTH) AF: 0.00190 AC: 4 AN: 2104

Alfa AF: 0.00202 Hom.: 1

Bravo AF: 0.00120

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000460 AC: 2

ESP6500EA AF: 0.00200 AC: 17

ExAC AF: 0.00122 AC: 144

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.22
Sift	Benign	0.12	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.44
MVP		0.67
MPC		0.065
ClinPred		0.054	T
GERP RS		3.1
PromoterAI		0.0026	Neutral
Varity_R		0.14
gMVP		0.50
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs200566665; hg19: chr5-110075055; COSMIC: COSV108185429; COSMIC: COSV108185429;