11-63166102-C-A

Variant summary

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

The NM_199352.6(SLC22A25):​c.1227G>T​(p.Gln409His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. Q409P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SLC22A25
NM_199352.6 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.271
Variant links:
Genes affected
SLC22A25 (HGNC:32935): (solute carrier family 22 member 25) Predicted to enable transmembrane transporter activity. Predicted to be involved in organic anion transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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=0.14532426).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC22A25NM_199352.6 linkc.1227G>T p.Gln409His missense_variant Exon 10 of 12 ENST00000306494.11 NP_955384.3 Q6T423
SLC22A25XM_047426917.1 linkc.*176G>T downstream_gene_variant XP_047282873.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC22A25ENST00000306494.11 linkc.1227G>T p.Gln409His missense_variant Exon 10 of 12 1 NM_199352.6 ENSP00000307443.6 Q6T423

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152224
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
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:
0.000478
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
250982
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135612
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461688
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000895
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000656
AC:
10
AN:
152342
Hom.:
0
Cov.:
33
AF XY:
0.0000940
AC XY:
7
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 04, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1227G>T (p.Q409H) alteration is located in exon 7 (coding exon 7) of the SLC22A25 gene. This alteration results from a G to T substitution at nucleotide position 1227, causing the glutamine (Q) at amino acid position 409 to be replaced by a histidine (H). 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
Uncertain
0.43
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
12
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.75
FATHMM_MKL
Benign
0.020
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.15
T
MetaSVM
Benign
-0.81
T
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Benign
0.26
T
PROVEAN
Uncertain
-3.7
D
REVEL
Benign
0.13
Sift
Uncertain
0.029
D
Sift4G
Benign
0.067
T
Polyphen
0.54
P
Vest4
0.29
MutPred
0.55
Gain of methylation at R406 (P = 0.0803);
MVP
0.14
MPC
0.028
ClinPred
0.66
D
GERP RS
-1.6
Varity_R
0.18
gMVP
0.34

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.

Other links and lift over

dbSNP: rs201794592; hg19: chr11-62933574; API