rs114859074

Variant names:

• chr5-110756712-G-A
• rs114859074
• NM_138773.4:c.631G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-110756712-G-A
• chr5-110756712-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138773.4(SLC25A46):​c.631G>A​(p.Val211Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,572,574 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V211A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.62
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008442342).
• BP6: Variant 5-110756712-G-A is Benign according to our data. Variant chr5-110756712-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00201 (306/151972) while in subpopulation NFE AF = 0.00324 (220/67930). AF 95% confidence interval is 0.00289. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.631G>A	p.Val211Met	missense	Exon 7 of 8	NP_620128.1	Q96AG3-1
	SLC25A46	NM_001303249.3		c.631G>A	p.Val211Met	missense	Exon 7 of 8	NP_001290178.1	Q96AG3-3
	SLC25A46	NM_001303250.3		c.358G>A	p.Val120Met	missense	Exon 7 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.631G>A	p.Val211Met	missense	Exon 7 of 8	ENSP00000348211.3	Q96AG3-1
	SLC25A46	ENST00000509432.1	TSL:2	c.-9G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000426604.1	B7Z6C8
	SLC25A46	ENST00000923605.1		c.631G>A	p.Val211Met	missense	Exon 7 of 8	ENSP00000593664.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 306 AN: 151854 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000761

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00324

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00257 AC: 566 AN: 220192 AF XY: 0.00260

Gnomad AFR exome AF: 0.000471

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00633

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00279 AC: 3963 AN: 1420602 Hom.: 14 Cov.: 29 AF XY: 0.00276 AC XY: 1946 AN XY: 705928

African (AFR) AF: 0.000357 AC: 11 AN: 30822

American (AMR) AF: 0.00137 AC: 48 AN: 35020

Ashkenazi Jewish (ASJ) AF: 0.00687 AC: 171 AN: 24908

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.00103 AC: 79 AN: 77052

European-Finnish (FIN) AF: 0.00191 AC: 101 AN: 52774

Middle Eastern (MID) AF: 0.00518 AC: 29 AN: 5598

European-Non Finnish (NFE) AF: 0.00304 AC: 3333 AN: 1097404

Other (OTH) AF: 0.00326 AC: 191 AN: 58528

GnomAD4 genome AF: 0.00201 AC: 306 AN: 151972 Hom.: 1 Cov.: 32 AF XY: 0.00201 AC XY: 149 AN XY: 74272

African (AFR) AF: 0.000434 AC: 18 AN: 41472

American (AMR) AF: 0.00177 AC: 27 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.000761 AC: 8 AN: 10518

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00324 AC: 220 AN: 67930

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

Alfa AF: 0.00299 Hom.: 4

Bravo AF: 0.00189

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00396 AC: 34

ExAC AF: 0.00276 AC: 335

ClinVar

ClinVar submissions

Significance: Likely benign

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)
-	-	1	SLC25A46-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.047	B
Vest4		0.40
MVP		0.53
MPC		0.059
ClinPred		0.0039	T
GERP RS		2.5
Varity_R		0.031
gMVP		0.55
Mutation Taster		=286/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs114859074; hg19: chr5-110092412;