rs200911718

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Splicing: ADA: 0.00002816

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.59

Publications

0 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]

SLC26A1 links:

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

IDUA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 283485.

BS2

High Homozygotes in GnomAdExome4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A1	NM_022042.4 link	c.*877C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000398516.3	NP_071325.2
IDUA	NM_000203.5 link	c.299+7G>A		splice_region_variant, intron_variant	Intron 2 of 13	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516.3 link	c.*877C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_022042.4	ENSP00000381528.2
IDUA	ENST00000514224.2 link	c.299+7G>A		splice_region_variant, intron_variant	Intron 2 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

415

AN:

152136

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00266

AC:

452

AN:

169908

AF XY:

0.00260

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 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.:

Cov.:

AF XY:

0.00442

AC XY:

3085

AN XY:

698288

show subpopulations

African (AFR)

AF:

0.000869

AC:

AN:

32206

American (AMR)

AF:

0.00240

AC:

AN:

37990

Ashkenazi Jewish (ASJ)

AF:

0.000710

AC:

AN:

25352

East Asian (EAS)

AF:

0.00

AC:

AN:

36894

South Asian (SAS)

AF:

0.00150

AC:

121

AN:

80936

European-Finnish (FIN)

AF:

0.000821

AC:

AN:

48724

Middle Eastern (MID)

AF:

0.00207

AC:

AN:

5320

European-Non Finnish (NFE)

AF:

0.00535

AC:

5814

AN:

1087184

Other (OTH)

AF:

0.00381

AC:

223

AN:

58460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

448

895

1343

1790

2238

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

232

464

696

928

1160

<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:

0.00272

AC:

414

AN:

152254

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

191

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000963

AC:

AN:

41558

American (AMR)

AF:

0.00287

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000848

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00446

AC:

303

AN:

67996

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

103

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00371

Hom.:

Bravo

AF:

0.00324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Sep 21, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Hereditary disease

Benign:1

May 01, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Mucopolysaccharidosis type 1

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

May 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

(source)

DANN

Benign

0.81

PhyloP100

2.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over