6-160132255-T-C

Position:

• chr6-160132255-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003057.3(SLC22A1):​c.539T>C​(p.Leu180Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC22A1 NM_003057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

SLC22A1 (HGNC:10963): (solute carrier family 22 member 1) 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. Two transcript variants encoding two different isoforms have been found for this gene, but only the longer variant encodes a functional transporter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC22A1	NM_003057.3	c.539T>C	p.Leu180Pro	missense_variant	3/11	ENST00000366963.9	NP_003048.1
SLC22A1	NM_153187.2	c.539T>C	p.Leu180Pro	missense_variant	3/10		NP_694857.1
SLC22A1	XM_005267103.3	c.539T>C	p.Leu180Pro	missense_variant	3/12		XP_005267160.1
SLC22A1	XM_006715552.3	c.539T>C	p.Leu180Pro	missense_variant	3/9		XP_006715615.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC22A1	ENST00000366963.9	c.539T>C	p.Leu180Pro	missense_variant	3/11	1	NM_003057.3	ENSP00000355930	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441354 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716002

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

The c.539T>C (p.L180P) alteration is located in exon 3 (coding exon 3) of the SLC22A1 gene. This alteration results from a T to C substitution at nucleotide position 539, causing the leucine (L) at amino acid position 180 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.5	H;H;H;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.1	D;.;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;.;D;D
Polyphen		0.98	D;D;D;.
Vest4		0.95
MutPred		0.77		Loss of stability (P = 0.0087);Loss of stability (P = 0.0087);Loss of stability (P = 0.0087);Loss of stability (P = 0.0087);
MVP		0.65
MPC		0.76
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.87

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: rs1780476293; hg19: chr6-160553287;