NM_021977.4:c.775G>A

Variant names:

• chr6-160408839-G-A
• rs1787126198
• NM_021977.4:c.775G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_021977.4(SLC22A3):​c.775G>A​(p.Gly259Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC22A3 NM_021977.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00
• Publications: 0 publications found

Genes affected

SLC22A3 (HGNC:10967): (solute carrier family 22 member 3) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. This gene is one of three similar cation transporter genes located in a cluster on chromosome 6. The encoded protein contains twelve putative transmembrane domains and is a plasma integral membrane protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021977.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A3	NM_021977.4	MANE Select	c.775G>A	p.Gly259Arg	missense	Exon 4 of 11	NP_068812.1	O75751

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A3	ENST00000275300.3	TSL:1 MANE Select	c.775G>A	p.Gly259Arg	missense	Exon 4 of 11	ENSP00000275300.2	O75751
	SLC22A3	ENST00000855214.1		c.865G>A	p.Gly289Arg	missense	Exon 5 of 12	ENSP00000525273.1
	SLC22A3	ENST00000855213.1		c.430-27941G>A		intron	N/A	ENSP00000525272.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		5.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.81		Gain of methylation at G259 (P = 0.0194)
MVP		0.87
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.94
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1787126198; hg19: chr6-160829871;