Variant 5-132294834-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003059.3(SLC22A4):c.218A>G(p.Asp73Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,014 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC22A4
NM_003059.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Variant links:

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]

SLC22A4 links:

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]

P4HA2 links:

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ACMG classification

Classification made for transcript

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=0.09886727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC22A4	NM_003059.3 linkuse as main transcript	c.218A>G	p.Asp73Gly	missense_variant	1/10	ENST00000200652.4
SLC22A4	XM_047417594.1 linkuse as main transcript	c.218A>G	p.Asp73Gly	missense_variant	1/8
SLC22A4	XM_011543589.3 linkuse as main transcript	c.218A>G	p.Asp73Gly	missense_variant	1/8
SLC22A4	XM_006714675.5 linkuse as main transcript	c.-207A>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SLC22A4	ENST00000200652.4 linkuse as main transcript	c.218A>G	p.Asp73Gly	missense_variant	1/10	1	NM_003059.3	P1
P4HA2	ENST00000471826.1 linkuse as main transcript	n.138+344T>C		intron_variant, non_coding_transcript_variant		1
P4HA2	ENST00000431054.5 linkuse as main transcript	c.78+344T>C		intron_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000126

AC:

AN:

237874

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000170

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458014

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725198

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The c.218A>G (p.D73G) alteration is located in exon 1 (coding exon 1) of the SLC22A4 gene. This alteration results from a A to G substitution at nucleotide position 218, causing the aspartic acid (D) at amino acid position 73 to be replaced by a glycine (G). 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

Benign

0.092

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

Eigen

Benign

-0.11

Eigen_PC

Benign

0.028

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.80

M_CAP

Benign

0.068

MetaRNN

Benign

0.099

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.73

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

REVEL

Benign

0.17

Sift

Benign

0.21

Sift4G

Benign

0.33

Polyphen

0.0010

Vest4

0.14

MutPred

0.47

Gain of MoRF binding (P = 0.0289);

MVP

0.71

MPC

1.2

ClinPred

0.13

GERP RS

4.5

Varity_R

0.13

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over