Genetic Variant NM_020041.3:c.374C>T (chr4-9996817-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP5_ModerateBP4

The NM_020041.3(SLC2A9):c.374C>T(p.Thr125Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,614,034 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T125T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SLC2A9
NM_020041.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.87

Publications

20 publications found

Variant links:

Genes affected

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC2A9 links:

SLC2A9-AS1 (HGNC:40636): (SLC2A9 antisense RNA 1)

SLC2A9-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 4-9996817-G-A is Pathogenic according to our data. Variant chr4-9996817-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 217421.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.27318722). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020041.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC2A9	NM_020041.3	MANE Select	c.374C>T	p.Thr125Met	missense	Exon 3 of 12	NP_064425.2
SLC2A9	NM_001001290.2		c.287C>T	p.Thr96Met	missense	Exon 4 of 13	NP_001001290.1	Q9NRM0-2
SLC2A9-AS1	NR_183861.1		n.308-2276G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC2A9	ENST00000264784.8	TSL:1 MANE Select	c.374C>T	p.Thr125Met	missense	Exon 3 of 12	ENSP00000264784.3	Q9NRM0-1
SLC2A9	ENST00000309065.7	TSL:1	c.287C>T	p.Thr96Met	missense	Exon 4 of 13	ENSP00000311383.3	Q9NRM0-2
SLC2A9	ENST00000505104.5	TSL:1	n.408C>T		non_coding_transcript_exon	Exon 4 of 12

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000139

AC:

AN:

251336

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111936

Other (OTH)

AF:

0.0000662

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000151

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41538

American (AMR)

AF:

0.00111

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000955

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hypouricemia, renal, 2 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.2

PhyloP100

7.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.52

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.45

MVP

0.79

MPC

0.52

ClinPred

0.44

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.62

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over