rs141213807

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_138773.4(SLC25A46):​c.767A>G​(p.Lys256Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00241 in 1,613,730 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)
Exomes 𝑓: 0.0025 ( 13 hom. )

Consequence

SLC25A46
NM_138773.4 missense

Scores

5
13

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.89

Publications

11 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_138773.4
BP4
Computational evidence support a benign effect (MetaRNN=0.012173474).
BP6
Variant 5-110761292-A-G is Benign according to our data. Variant chr5-110761292-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 475800.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 = 0.00187 (284/152160) while in subpopulation NFE AF = 0.00285 (194/67976). AF 95% confidence interval is 0.00252. There are 2 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 2 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

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
SLC25A46
NM_138773.4
MANE Select
c.767A>Gp.Lys256Arg
missense
Exon 8 of 8NP_620128.1
SLC25A46
NM_001303250.3
c.494A>Gp.Lys165Arg
missense
Exon 8 of 8NP_001290179.1
SLC25A46
NR_138151.2
n.1006A>G
non_coding_transcript_exon
Exon 9 of 9

Ensembl Transcripts

Selected
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
SLC25A46
ENST00000355943.8
TSL:1 MANE Select
c.767A>Gp.Lys256Arg
missense
Exon 8 of 8ENSP00000348211.3
SLC25A46
ENST00000504098.1
TSL:5
c.329A>Gp.Lys110Arg
missense
Exon 7 of 7ENSP00000425708.1
SLC25A46
ENST00000513807.5
TSL:2
c.281A>Gp.Lys94Arg
missense
Exon 8 of 8ENSP00000421134.1

Frequencies

GnomAD3 genomes
AF:
0.00187
AC:
284
AN:
152042
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000410
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00217
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00254
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00285
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.00216
AC:
543
AN:
250884
AF XY:
0.00234
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.00139
Gnomad ASJ exome
AF:
0.00407
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00287
Gnomad NFE exome
AF:
0.00304
Gnomad OTH exome
AF:
0.00164
GnomAD4 exome
AF:
0.00247
AC:
3609
AN:
1461570
Hom.:
13
Cov.:
32
AF XY:
0.00245
AC XY:
1778
AN XY:
727100
show subpopulations
African (AFR)
AF:
0.000568
AC:
19
AN:
33454
American (AMR)
AF:
0.00136
AC:
61
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00337
AC:
88
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.00108
AC:
93
AN:
86250
European-Finnish (FIN)
AF:
0.00234
AC:
125
AN:
53416
Middle Eastern (MID)
AF:
0.00590
AC:
34
AN:
5764
European-Non Finnish (NFE)
AF:
0.00274
AC:
3046
AN:
1111794
Other (OTH)
AF:
0.00237
AC:
143
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
193
387
580
774
967
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
102
204
306
408
510
<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
AF:
0.00187
AC:
284
AN:
152160
Hom.:
2
Cov.:
32
AF XY:
0.00198
AC XY:
147
AN XY:
74384
show subpopulations
African (AFR)
AF:
0.000409
AC:
17
AN:
41550
American (AMR)
AF:
0.00217
AC:
33
AN:
15240
Ashkenazi Jewish (ASJ)
AF:
0.00115
AC:
4
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5166
South Asian (SAS)
AF:
0.000415
AC:
2
AN:
4824
European-Finnish (FIN)
AF:
0.00254
AC:
27
AN:
10614
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00285
AC:
194
AN:
67976
Other (OTH)
AF:
0.00237
AC:
5
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.506
Heterozygous variant carriers
0
12
24
37
49
61
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00255
Hom.:
5
Bravo
AF:
0.00186
TwinsUK
AF:
0.00189
AC:
7
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.00114
AC:
5
ESP6500EA
AF:
0.00302
AC:
26
ExAC
AF:
0.00196
AC:
238
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00431
EpiControl
AF:
0.00468

ClinVar

ClinVar submissions as Germline

Significance:Likely benign
Revision:criteria provided, multiple submitters, no conflicts
View on ClinVar
Pathogenic
VUS
Benign
Condition
-
-
2
not provided (2)
-
-
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
0.11
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0062
T
Eigen
Benign
0.021
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.012
T
MetaSVM
Benign
-0.34
T
MutationAssessor
Benign
1.6
L
PhyloP100
5.9
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.40
N
REVEL
Benign
0.24
Sift
Benign
0.76
T
Sift4G
Benign
0.78
T
Polyphen
0.0080
B
Vest4
0.21
MVP
0.56
MPC
0.16
ClinPred
0.017
T
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.11
gMVP
0.49
Mutation Taster
=85/15
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

Publications

Other links and lift over

dbSNP: rs141213807; hg19: chr5-110096992; COSMIC: COSV100582585; COSMIC: COSV100582585; API