rs121908323

Variant names:

• chr4-9887623-G-A
• rs121908323
• NM_020041.3:c.1235C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-9887623-G-A
• chr4-9887623-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_020041.3(SLC2A9):​c.1235C>T​(p.Pro412Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P412R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: SLC2A9 NM_020041.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hypouricemia, renal, 2

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary renal hypouricemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-9887623-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4598.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A9	NM_020041.3	MANE Select	c.1235C>T	p.Pro412Leu	missense	Exon 10 of 12	NP_064425.2
	SLC2A9	NM_001001290.2		c.1148C>T	p.Pro383Leu	missense	Exon 11 of 13	NP_001001290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC2A9	ENST00000264784.8	TSL:1 MANE Select	c.1235C>T	p.Pro412Leu	missense	Exon 10 of 12	ENSP00000264784.3
	SLC2A9	ENST00000309065.7	TSL:1	c.1148C>T	p.Pro383Leu	missense	Exon 11 of 13	ENSP00000311383.3
	SLC2A9	ENST00000505104.5	TSL:1	n.1269C>T		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403960 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 692382

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

African (AFR) AF: 0.00 AC: 0 AN: 32038

American (AMR) AF: 0.00 AC: 0 AN: 38348

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24156

East Asian (EAS) AF: 0.00 AC: 0 AN: 36682

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081384

Other (OTH) AF: 0.00 AC: 0 AN: 57990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.20	T
Polyphen		0.36	B
Vest4		0.78
MutPred		0.65		Loss of helix (P = 0.1706)
MVP		0.78
MPC		0.52
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.52
gMVP		0.91
Mutation Taster		=34/66	disease causing

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

Other links and lift over

dbSNP: rs121908323; hg19: chr4-9889247; COSMIC: COSV105106125;