chr6-160122009-T-C

Variant names:

• chr6-160122009-T-C
• rs1440356481
• NM_003057.3:c.74T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003057.3(SLC22A1):​c.74T>C​(p.Leu25Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,818 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: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: SLC22A1 NM_003057.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57
• Publications: 1 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003057.3. 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
	SLC22A1	NM_003057.3	MANE Select	c.74T>C	p.Leu25Ser	missense	Exon 1 of 11	NP_003048.1	O15245-1
	SLC22A1	NM_153187.2		c.74T>C	p.Leu25Ser	missense	Exon 1 of 10	NP_694857.1	O15245-2
	SLC22A1	NM_001437335.1		c.74T>C	p.Leu25Ser	missense	Exon 1 of 9	NP_001424264.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC22A1	ENST00000366963.9	TSL:1 MANE Select	c.74T>C	p.Leu25Ser	missense	Exon 1 of 11	ENSP00000355930.4	O15245-1
	SLC22A1	ENST00000898298.1		c.74T>C	p.Leu25Ser	missense	Exon 1 of 12	ENSP00000568357.1
	SLC22A1	ENST00000898304.1		c.74T>C	p.Leu25Ser	missense	Exon 1 of 12	ENSP00000568363.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251432 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461818 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.59		Loss of stability (P = 0.1167)
MVP		0.58
MPC		0.69
ClinPred		0.97	D
GERP RS		4.3
PromoterAI		-0.0040	Neutral
Varity_R		0.41
gMVP		0.81
Mutation Taster		=83/17	polymorphism

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: rs1440356481; hg19: chr6-160543041;