rs73219719

Variant summary

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

The NM_022042.4(SLC26A1):​c.1115G>T​(p.Arg372Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,580,256 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

SLC26A1
NM_022042.4 missense

Scores

2
8
9

Clinical Significance

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

Conservation

PhyloP100: 0.0440

Publications

13 publications found
Variant links:
Genes affected
SLC26A1 (HGNC:10993): (solute carrier family 26 member 1) This gene is a member of a family of sulfate/anion transporter genes. Family members are well conserved in their genomic (number and size of exons) and protein (aa length among species) structures, but have markedly different tissue expression patterns. This gene is primarily expressed in the liver, pancreas, and brain. Three splice variants that encode different isoforms have been identified. [provided by RefSeq, Jul 2008]
IDUA (HGNC:5391): (alpha-L-iduronidase) This gene encodes an enzyme that hydrolyzes the terminal alpha-L-iduronic acid residues of two glycosaminoglycans, dermatan sulfate and heparan sulfate. This hydrolysis is required for the lysosomal degradation of these glycosaminoglycans. Mutations in this gene that result in enzymatic deficiency lead to the autosomal recessive disease mucopolysaccharidosis type I (MPS I). [provided by RefSeq, Jul 2008]
IDUA Gene-Disease associations (from GenCC):
  • mucopolysaccharidosis type 1
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
  • Scheie syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
  • Hurler syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
  • Hurler-Scheie syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

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, 0.771

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A1NM_022042.4 linkc.1115G>T p.Arg372Leu missense_variant Exon 3 of 3 ENST00000398516.3 NP_071325.2 Q9H2B4-1
IDUANM_000203.5 linkc.299+1875C>A intron_variant Intron 2 of 13 ENST00000514224.2 NP_000194.2 P35475-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A1ENST00000398516.3 linkc.1115G>T p.Arg372Leu missense_variant Exon 3 of 3 1 NM_022042.4 ENSP00000381528.2 Q9H2B4-1
IDUAENST00000514224.2 linkc.299+1875C>A intron_variant Intron 2 of 13 2 NM_000203.5 ENSP00000425081.2 P35475-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152250
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000363
AC:
7
AN:
192628
AF XY:
0.0000478
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000348
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000728
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000462
AC:
66
AN:
1428006
Hom.:
0
Cov.:
71
AF XY:
0.0000438
AC XY:
31
AN XY:
707208
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32920
American (AMR)
AF:
0.0000252
AC:
1
AN:
39670
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25506
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38052
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81760
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49336
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5582
European-Non Finnish (NFE)
AF:
0.0000575
AC:
63
AN:
1096080
Other (OTH)
AF:
0.0000338
AC:
2
AN:
59100
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.470
Heterozygous variant carriers
0
5
10
15
20
25
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000197
AC:
3
AN:
152250
Hom.:
0
Cov.:
35
AF XY:
0.0000134
AC XY:
1
AN XY:
74384
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41460
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5208
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000294
AC:
2
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome 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
Alfa
AF:
0.00000472
Hom.:
12
Bravo
AF:
0.0000416
ExAC
AF:
0.0000168
AC:
2

ClinVar

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

Submissions by phenotype

Hyperoxaluria Uncertain:1
May 15, 2023
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

not provided Uncertain:1
Mar 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 372 of the SLC26A1 protein (p.Arg372Leu). This variant is present in population databases (rs73219719, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with SLC26A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2502382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC26A1 protein function with a negative predictive value of 80%. 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
Benign
0.13
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.71
D;D
Eigen
Benign
-0.062
Eigen_PC
Benign
-0.24
FATHMM_MKL
Benign
0.26
N
LIST_S2
Uncertain
0.93
.;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Uncertain
0.24
D
MutationAssessor
Uncertain
2.0
M;M
PhyloP100
0.044
PrimateAI
Benign
0.34
T
PROVEAN
Uncertain
-4.2
D;D
REVEL
Uncertain
0.41
Sift
Benign
0.050
D;D
Sift4G
Uncertain
0.025
D;D
Polyphen
0.90
P;P
Vest4
0.55
MVP
0.91
MPC
0.49
ClinPred
0.30
T
GERP RS
3.4
Varity_R
0.23
gMVP
0.75
Mutation Taster
=98/2
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs73219719; hg19: chr4-983612; COSMIC: COSV56102473; COSMIC: COSV56102473; API