Genetic Variant NM_138773.4:c.620C>G (chr5-110755521-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138773.4(SLC25A46):c.620C>G(p.Ser207Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000708 in 1,413,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S207Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SLC25A46
NM_138773.4 missense, splice_region

Scores

Splicing: ADA: 0.0002592

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

Publications

0 publications found

Variant links:

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

SLC25A46 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12675476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4 link	c.620C>G	p.Ser207Cys	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000355943.8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3 link	c.620C>G	p.Ser207Cys	missense_variant, splice_region_variant	Exon 6 of 8		NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3 link	c.347C>G	p.Ser116Cys	missense_variant, splice_region_variant	Exon 6 of 8		NP_001290179.1	Q96AG3B4DY98
SLC25A46	NR_138151.2 link	n.733C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A46	ENST00000355943.8 link	c.620C>G	p.Ser207Cys	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_138773.4	ENSP00000348211.3		Q96AG3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1413250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

703292

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30904

American (AMR)

AF:

0.00

AC:

AN:

36744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24848

East Asian (EAS)

AF:

0.00

AC:

AN:

38460

South Asian (SAS)

AF:

0.00

AC:

AN:

78274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1087180

Other (OTH)

AF:

0.00

AC:

AN:

58416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0031

T;T;.;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.030

.;N;N;.

PhyloP100

3.9

PrimateAI

Benign

0.36

PROVEAN

Benign

2.2

N;N;N;N

REVEL

Benign

0.20

Sift

Benign

0.24

T;T;T;T

Sift4G

Benign

0.69

T;T;T;T

Polyphen

0.0

.;B;.;.

Vest4

0.32

MutPred

0.63

.;Gain of methylation at K206 (P = 0.0163);Gain of methylation at K206 (P = 0.0163);.;

MVP

0.55

MPC

0.056

ClinPred

0.63

GERP RS

4.7

PromoterAI

0.013

Neutral

(source)

Varity_R

0.12

gMVP

0.63

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.19

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over