rs3733591

Positions:

• chr4-9920506-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020041.3(SLC2A9):​c.881G>A​(p.Arg294His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,614,018 control chromosomes in the GnomAD database, including 43,797 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3490 hom., cov: 33)
  • Exomes 𝑓: 0.21 (40307 hom.)
• Consequence: SLC2A9 NM_020041.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0290

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.065905E-6).
• BP6: Variant 4-9920506-C-T is Benign according to our data. Variant chr4-9920506-C-T is described in ClinVar as [Benign]. Clinvar id is 350213.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-9920506-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC2A9	NM_020041.3	c.881G>A	p.Arg294His	missense_variant	7/12	ENST00000264784.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC2A9	ENST00000264784.8	c.881G>A	p.Arg294His	missense_variant	7/12	1	NM_020041.3	A2
SLC2A9	ENST00000309065.7	c.794G>A	p.Arg265His	missense_variant	8/13	1		P2
SLC2A9	ENST00000505104.5	n.915G>A		non_coding_transcript_exon_variant	8/12	1
SLC2A9	ENST00000506583.5	c.794G>A	p.Arg265His	missense_variant	9/14	5		P2

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27517 AN: 152118 Hom.: 3490 Cov.: 33

Gnomad AFR AF: 0.0689

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.178

GnomAD3 exomes AF: 0.246 AC: 61854 AN: 251088 Hom.: 10057 AF XY: 0.252 AC XY: 34228 AN XY: 135788

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.671

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.214 AC: 313476 AN: 1461782 Hom.: 40307 Cov.: 38 AF XY: 0.219 AC XY: 159222 AN XY: 727190

Gnomad4 AFR exome AF: 0.0624

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.162

Gnomad4 EAS exome AF: 0.691

Gnomad4 SAS exome AF: 0.361

Gnomad4 FIN exome AF: 0.240

Gnomad4 NFE exome AF: 0.190

Gnomad4 OTH exome AF: 0.215

GnomAD4 genome AF: 0.181 AC: 27522 AN: 152236 Hom.: 3490 Cov.: 33 AF XY: 0.190 AC XY: 14133 AN XY: 74442

Gnomad4 AFR AF: 0.0688

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.147

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.181

Alfa AF: 0.196 Hom.: 8757

Bravo AF: 0.171

TwinsUK AF: 0.201 AC: 746

ALSPAC AF: 0.186 AC: 717

ESP6500AA AF: 0.0713 AC: 314

ESP6500EA AF: 0.189 AC: 1629

ExAC AF: 0.245 AC: 29794

Asia WGS AF: 0.454 AC: 1573 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.182

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 19723617, 21658257) -

Hypouricemia, renal, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.77	T;.;T
MetaRNN	Benign	0.0000071	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.094
MPC		0.14
ClinPred		0.022	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs3733591; hg19: chr4-9922130; COSMIC: COSV53319201; COSMIC: COSV53319201;