5-132294825-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003059.3(SLC22A4):c.209G>C(p.Arg70Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 1,458,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SLC22A4 NM_003059.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.607

Genes affected

SLC22A4 (HGNC:10968): (solute carrier family 22 member 4) 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. The encoded protein is an organic cation transporter and plasma integral membrane protein containing eleven putative transmembrane domains as well as a nucleotide-binding site motif. Transport by this protein is at least partially ATP-dependent. [provided by RefSeq, Jul 2008]

P4HA2 (HGNC:8547): (prolyl 4-hydroxylase subunit alpha 2) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14007086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A4	NM_003059.3	c.209G>C	p.Arg70Pro	missense_variant	1/10	ENST00000200652.4
SLC22A4	XM_047417594.1	c.209G>C	p.Arg70Pro	missense_variant	1/8
SLC22A4	XM_011543589.3	c.209G>C	p.Arg70Pro	missense_variant	1/8
SLC22A4	XM_006714675.5	c.-216G>C		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A4	ENST00000200652.4	c.209G>C	p.Arg70Pro	missense_variant	1/10	1	NM_003059.3	P1
P4HA2	ENST00000471826.1	n.138+353C>G		intron_variant, non_coding_transcript_variant		1
P4HA2	ENST00000431054.5	c.78+353C>G		intron_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000828 AC: 2 AN: 241596 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000926

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458862 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.209G>C (p.R70P) alteration is located in exon 1 (coding exon 1) of the SLC22A4 gene. This alteration results from a G to C substitution at nucleotide position 209, causing the arginine (R) at amino acid position 70 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SLC22A4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 70 of the SLC22A4 protein (p.Arg70Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.072	T
Sift4G	Benign	0.090	T
Polyphen		0.0080	B
Vest4		0.32
MutPred		0.52		Loss of MoRF binding (P = 0.0033);
MVP		0.76
MPC		1.3
ClinPred		0.39	T
GERP RS		-1.3
Varity_R		0.19
gMVP		0.90

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: rs749095440; hg19: chr5-131630518; COSMIC: COSV52359328; COSMIC: COSV52359328;