5-110755521-C-T

Variant names:

Variant summary

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

The NM_138773.4(SLC25A46):c.620C>T(p.Ser207Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000849 in 1,413,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000085 ( 0 hom. )

Consequence

SLC25A46
NM_138773.4 missense, splice_region

Scores

Splicing: ADA: 0.09819

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.90

Publications

1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A46	NM_138773.4 link	c.620C>T	p.Ser207Phe	missense_variant, splice_region_variant	Exon 6 of 8	ENST00000355943.8	NP_620128.1	Q96AG3-1
SLC25A46	NM_001303249.3 link	c.620C>T	p.Ser207Phe	missense_variant, splice_region_variant	Exon 6 of 8		NP_001290178.1	Q96AG3-3
SLC25A46	NM_001303250.3 link	c.347C>T	p.Ser116Phe	missense_variant, splice_region_variant	Exon 6 of 8		NP_001290179.1	Q96AG3B4DY98
SLC25A46	NR_138151.2 link	n.733C>T		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>T	p.Ser207Phe	missense_variant, splice_region_variant	Exon 6 of 8	1	NM_138773.4	ENSP00000348211.3		Q96AG3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000889

AC:

AN:

225056

AF XY:

0.00000816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000618

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000849

AC:

AN:

1413250

Hom.:

Cov.:

AF XY:

0.00000711

AC XY:

AN XY:

703292

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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:

0.0000260

AC:

AN:

38460

South Asian (SAS)

AF:

0.0000383

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:

0.00000736

AC:

AN:

1087180

Other (OTH)

AF:

0.00

AC:

AN:

58416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000897414), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.050

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.079

T;T;.;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.057

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Uncertain

0.018

MutationAssessor

Benign

1.4

.;L;L;.

PhyloP100

3.9

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

N;N;N;N

REVEL

Uncertain

0.50

Sift

Benign

0.039

D;D;T;D

Sift4G

Benign

0.065

T;D;D;D

Polyphen

0.83

.;P;.;.

Vest4

0.49

MutPred

0.67

.;Gain of methylation at K206 (P = 0.0531);Gain of methylation at K206 (P = 0.0531);.;

MVP

0.73

MPC

0.14

ClinPred

0.52

GERP RS

4.7

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.15

gMVP

0.80

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.098

dbscSNV1_RF

Benign

0.25

SpliceAI score (max)

0.010

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