dbSNP rs147498923: SLC26A1:c.*878G>A (chr4-987955-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000203.5(IDUA):c.299+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00956 in 1,566,936 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★). The gene IDUA is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0092 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0096 ( 105 hom. )

Consequence

IDUA
NM_000203.5 splice_region, intron

Scores

Splicing: ADA: 0.00003218

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 1.03

Publications

2 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: Myriad Women’s Health, ClinGen
Scheie syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
Hurler syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
Hurler-Scheie syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

IDUA links:

Genome browser will be placed here

ACMG classification

Specifications for IDUA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 4-987955-C-T is Benign according to our data. Variant chr4-987955-C-T is described in ClinVar as Benign. ClinVar VariationId is 92640.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00923 (1405/152258) while in subpopulation NFE AF = 0.0119 (810/67998). AF 95% confidence interval is 0.0112. There are 14 homozygotes in GnomAd4. There are 739 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000203.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC26A1	NM_022042.4	MANE Select	c.*878G>A	3_prime_UTR	Exon 3 of 3	NP_071325.2
IDUA	NM_000203.5	MANE Select	c.299+6C>T	splice_region intron	N/A	NP_000194.2	P35475-1
SLC26A1	NM_213613.4		c.*878G>A	3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*878G>A	3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1
SLC26A1	ENST00000361661.6	TSL:1	c.*878G>A	3_prime_UTR	Exon 4 of 4	ENSP00000354721.2	Q9H2B4-1
IDUA	ENST00000514224.2	TSL:2 MANE Select	c.299+6C>T	splice_region intron	N/A	ENSP00000425081.2	P35475-1

Frequencies

GnomAD3 genomes

AF:

0.00923

AC:

1405

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.0304

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0101

AC:

1744

AN:

172956

AF XY:

0.0106

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00331

Gnomad ASJ exome

AF:

0.00765

Gnomad EAS exome

AF:

0.0000765

Gnomad FIN exome

AF:

0.0304

Gnomad NFE exome

AF:

0.0126

Gnomad OTH exome

AF:

0.0133

GnomAD4 exome

AF:

0.00960

AC:

13581

AN:

1414678

Hom.:

105

Cov.:

AF XY:

0.00956

AC XY:

6687

AN XY:

699228

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

32258

American (AMR)

AF:

0.00366

AC:

140

AN:

38266

Ashkenazi Jewish (ASJ)

AF:

0.00788

AC:

200

AN:

25368

East Asian (EAS)

AF:

0.0000270

AC:

AN:

36996

South Asian (SAS)

AF:

0.00541

AC:

439

AN:

81154

European-Finnish (FIN)

AF:

0.0306

AC:

1494

AN:

48806

Middle Eastern (MID)

AF:

0.0272

AC:

146

AN:

5360

European-Non Finnish (NFE)

AF:

0.00969

AC:

10543

AN:

1087964

Other (OTH)

AF:

0.00950

AC:

556

AN:

58506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

870

1739

2609

3478

4348

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.00923

AC:

1405

AN:

152258

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

739

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41552

American (AMR)

AF:

0.00732

AC:

112

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00664

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00539

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0304

AC:

323

AN:

10614

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

810

AN:

67998

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

154

230

307

384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00942

Hom.:

Bravo

AF:

0.00671

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (5)

Mucopolysaccharidosis type 1 (3)

Hurler syndrome (1)

Nephrolithiasis, calcium oxalate (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

1.0

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over