NM_022042.4:c.*877C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_022042.4(SLC26A1):​c.*877C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,565,320 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0045 ( 31 hom. )

Consequence

SLC26A1
NM_022042.4 3_prime_UTR

Scores

2
Splicing: ADA: 0.00002816
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.59
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 4-987956-G-A is Benign according to our data. Variant chr4-987956-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283485.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr4-987956-G-A is described in Lovd as [Likely_benign].
BS2
High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A1NM_022042.4 linkc.*877C>T 3_prime_UTR_variant Exon 3 of 3 ENST00000398516.3 NP_071325.2 Q9H2B4-1
IDUANM_000203.5 linkc.299+7G>A splice_region_variant, 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 linkc.*877C>T 3_prime_UTR_variant Exon 3 of 3 1 NM_022042.4 ENSP00000381528.2 Q9H2B4-1
IDUAENST00000514224.2 linkc.299+7G>A splice_region_variant, intron_variant Intron 2 of 13 2 NM_000203.5 ENSP00000425081.2 P35475-1

Frequencies

GnomAD3 genomes
AF:
0.00273
AC:
415
AN:
152136
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00294
Gnomad ASJ
AF:
0.000577
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.000848
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00446
Gnomad OTH
AF:
0.00526
GnomAD3 exomes
AF:
0.00266
AC:
452
AN:
169908
Hom.:
2
AF XY:
0.00260
AC XY:
238
AN XY:
91650
show subpopulations
Gnomad AFR exome
AF:
0.00163
Gnomad AMR exome
AF:
0.00203
Gnomad ASJ exome
AF:
0.000700
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00132
Gnomad FIN exome
AF:
0.000680
Gnomad NFE exome
AF:
0.00477
Gnomad OTH exome
AF:
0.00278
GnomAD4 exome
AF:
0.00449
AC:
6346
AN:
1413066
Hom.:
31
Cov.:
30
AF XY:
0.00442
AC XY:
3085
AN XY:
698288
show subpopulations
Gnomad4 AFR exome
AF:
0.000869
Gnomad4 AMR exome
AF:
0.00240
Gnomad4 ASJ exome
AF:
0.000710
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00150
Gnomad4 FIN exome
AF:
0.000821
Gnomad4 NFE exome
AF:
0.00535
Gnomad4 OTH exome
AF:
0.00381
GnomAD4 genome
AF:
0.00272
AC:
414
AN:
152254
Hom.:
1
Cov.:
33
AF XY:
0.00257
AC XY:
191
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.000963
Gnomad4 AMR
AF:
0.00287
Gnomad4 ASJ
AF:
0.000577
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.000848
Gnomad4 NFE
AF:
0.00446
Gnomad4 OTH
AF:
0.00521
Alfa
AF:
0.00371
Hom.:
0
Bravo
AF:
0.00324

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 1 Uncertain:1Benign:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Benign:2
Jul 27, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: IDUA c.299+7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0027 in 169908 control chromosomes, predominantly at a frequency of 0.0048 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.78 fold of the estimated maximal expected allele frequency for a pathogenic variant in IDUA causing Mucopolysaccharidosis Type 1 phenotype (0.0027), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.299+7G>A in individuals affected with Mucopolysaccharidosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=1; likely benign, n=2, VUS, n=1). Based on the evidence outlined above, the variant was classified as benign. -

Sep 21, 2015
Eurofins Ntd Llc (ga)
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary disease Benign:1
May 01, 2020
Natera, Inc.
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:1
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

IDUA: BP4, BS2; SLC26A1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
11
DANN
Benign
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000028
dbscSNV1_RF
Benign
0.028
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: rs200911718; hg19: chr4-981744; API