rs200911718

Variant names:

• chr4-987956-G-A
• rs200911718
• NM_022042.4:c.*877C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-987956-G-A
• chr4-987956-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):​c.299+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,565,320 control chromosomes in the GnomAD database, including 32 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (31 hom.)
• Consequence: IDUA NM_000203.5 splice_region, intron
• 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

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: 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

ACMG classification

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 283485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00272 (414/152254) while in subpopulation NFE AF = 0.00446 (303/67996). AF 95% confidence interval is 0.00404. There are 1 homozygotes in GnomAd4. There are 191 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A1	NM_022042.4	MANE Select	c.*877C>T		3_prime_UTR	Exon 3 of 3	NP_071325.2
	IDUA	NM_000203.5	MANE Select	c.299+7G>A		splice_region intron	N/A	NP_000194.2	P35475-1
	SLC26A1	NM_213613.4		c.*877C>T		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*877C>T		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1
	SLC26A1	ENST00000361661.6	TSL:1	c.*877C>T		3_prime_UTR	Exon 4 of 4	ENSP00000354721.2	Q9H2B4-1
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.299+7G>A		splice_region intron	N/A	ENSP00000425081.2	P35475-1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 415 AN: 152136 Hom.: 1 Cov.: 33

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

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.: 31 Cov.: 30 AF XY: 0.00442 AC XY: 3085 AN XY: 698288

African (AFR) AF: 0.000869 AC: 28 AN: 32206

American (AMR) AF: 0.00240 AC: 91 AN: 37990

Ashkenazi Jewish (ASJ) AF: 0.000710 AC: 18 AN: 25352

East Asian (EAS) AF: 0.00 AC: 0 AN: 36894

South Asian (SAS) AF: 0.00150 AC: 121 AN: 80936

European-Finnish (FIN) AF: 0.000821 AC: 40 AN: 48724

Middle Eastern (MID) AF: 0.00207 AC: 11 AN: 5320

European-Non Finnish (NFE) AF: 0.00535 AC: 5814 AN: 1087184

Other (OTH) AF: 0.00381 AC: 223 AN: 58460

GnomAD4 genome AF: 0.00272 AC: 414 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.00257 AC XY: 191 AN XY: 74456

African (AFR) AF: 0.000963 AC: 40 AN: 41558

American (AMR) AF: 0.00287 AC: 44 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00446 AC: 303 AN: 67996

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00371 Hom.: 0

Bravo AF: 0.00324

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Hereditary disease (1)
-	-	1	Mucopolysaccharidosis type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.81
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200911718; hg19: chr4-981744;