5-132294902-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003059.3(SLC22A4):​c.286G>C​(p.Gly96Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,596,338 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SLC22A4
NM_003059.3 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.32

Publications

0 publications found
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]
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 Gene-Disease associations (from GenCC):
  • myopia
    Inheritance: AD Classification: STRONG Submitted by: G2P
  • myopia 25, autosomal dominant
    Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC22A4NM_003059.3 linkc.286G>C p.Gly96Arg missense_variant Exon 1 of 10 ENST00000200652.4 NP_003050.2 Q9H015
SLC22A4XM_047417594.1 linkc.286G>C p.Gly96Arg missense_variant Exon 1 of 8 XP_047273550.1
SLC22A4XM_011543589.3 linkc.286G>C p.Gly96Arg missense_variant Exon 1 of 8 XP_011541891.1
SLC22A4XM_006714675.5 linkc.-139G>C 5_prime_UTR_variant Exon 1 of 9 XP_006714738.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC22A4ENST00000200652.4 linkc.286G>C p.Gly96Arg missense_variant Exon 1 of 10 1 NM_003059.3 ENSP00000200652.3 Q9H015
P4HA2ENST00000471826.1 linkn.138+276C>G intron_variant Intron 1 of 3 1
P4HA2ENST00000431054.5 linkc.78+276C>G intron_variant Intron 1 of 5 4 ENSP00000391257.1 E7EPI9

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000145
AC:
3
AN:
206660
AF XY:
0.0000176
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000328
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000226
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000229
AC:
33
AN:
1444126
Hom.:
0
Cov.:
31
AF XY:
0.0000251
AC XY:
18
AN XY:
717252
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33114
American (AMR)
AF:
0.0000720
AC:
3
AN:
41672
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25822
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38778
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84720
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50228
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5706
European-Non Finnish (NFE)
AF:
0.0000263
AC:
29
AN:
1104404
Other (OTH)
AF:
0.0000168
AC:
1
AN:
59682
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.498
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152212
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.000131
AC:
2
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.00000835
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 01, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.286G>C (p.G96R) 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 286, causing the glycine (G) at amino acid position 96 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Jan 06, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 96 of the SLC22A4 protein (p.Gly96Arg). This variant is present in population databases (rs757815454, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SLC22A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2174633). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.40
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.15
T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Uncertain
0.10
D
MutationAssessor
Uncertain
2.8
M
PhyloP100
4.3
PrimateAI
Uncertain
0.74
T
PROVEAN
Pathogenic
-5.4
D
REVEL
Uncertain
0.51
Sift
Benign
0.057
T
Sift4G
Uncertain
0.0030
D
Polyphen
0.99
D
Vest4
0.82
MutPred
0.49
Gain of solvent accessibility (P = 2e-04);
MVP
0.94
MPC
2.1
ClinPred
0.98
D
GERP RS
4.4
PromoterAI
-0.025
Neutral
Varity_R
0.55
gMVP
0.70
Mutation Taster
=61/39
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

Publications

Other links and lift over

dbSNP: rs757815454; hg19: chr5-131630595; API