Genetic Variant NM_003562.5:c.671G>A (chr17-4938220-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003562.5(SLC25A11):c.671G>A(p.Cys224Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000886 in 1,613,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

SLC25A11
NM_003562.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.89

Publications

0 publications found

Variant links:

Genes affected

SLC25A11 (HGNC:10981): (solute carrier family 25 member 11) The oxoglutarate/malate carrier transports 2-oxoglutarate across the inner membranes of mitochondria in an electroneutral exchange for malate or other dicarboxylic acids (summary by Iacobazzi et al., 1992 [PubMed 1457818]).[supplied by OMIM, Jan 2011]

SLC25A11 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pheochromocytoma/paraganglioma syndrome 6
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SLC25A11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.048953533).

BP6

Variant 17-4938220-C-T is Benign according to our data. Variant chr17-4938220-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2383154.

BS2

High AC in GnomAd4 at 14 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003562.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A11	NM_003562.5	MANE Select	c.671G>A	p.Cys224Tyr	missense	Exon 6 of 8	NP_003553.2
SLC25A11	NM_001165417.2		c.638G>A	p.Cys213Tyr	missense	Exon 6 of 8	NP_001158889.1
SLC25A11	NM_001165418.2		c.518G>A	p.Cys173Tyr	missense	Exon 5 of 7	NP_001158890.1	Q02978-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC25A11	ENST00000225665.12	TSL:1 MANE Select	c.671G>A	p.Cys224Tyr	missense	Exon 6 of 8	ENSP00000225665.7	Q02978-1
SLC25A11	ENST00000940187.1		c.755G>A	p.Cys252Tyr	missense	Exon 5 of 7	ENSP00000610246.1
SLC25A11	ENST00000576951.1	TSL:5	c.638G>A	p.Cys213Tyr	missense	Exon 6 of 8	ENSP00000458993.1	I3L1P8

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000196

AC:

AN:

250414

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00398

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1461654

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00348

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111894

Other (OTH)

AF:

0.000232

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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

AF:

0.0000920

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000608

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.054

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.052

MetaRNN

Benign

0.049

MetaSVM

Benign

-0.68

MutationAssessor

Benign

1.4

PhyloP100

6.9

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.49

Sift

Benign

0.31

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.81

MVP

0.78

MPC

1.5

ClinPred

0.12

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.98

Mutation Taster

=48/52

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over