4-987243-G-A

Variant names:

• chr4-987243-G-A
• rs1264013707
• NM_000203.5:c.158+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000203.5(IDUA):​c.158+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000367 in 1,362,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: IDUA NM_000203.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.95
• Publications: 1 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• nephrolithiasis susceptibility caused by SLC26A1

  Inheritance: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-987243-G-A is Pathogenic according to our data. Variant chr4-987243-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 526835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.158+1G>A		splice_donor intron	N/A	NP_000194.2
	SLC26A1	NM_134425.4		c.576+3885C>T		intron	N/A	NP_602297.1
	IDUA	NR_110313.1		n.246+1G>A		splice_donor intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.158+1G>A		splice_donor intron	N/A	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.158+1G>A		splice_donor intron	N/A	ENSP00000247933.4
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3885C>T		intron	N/A	ENSP00000381532.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000900 AC: 1 AN: 111074 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000242

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1362012 Hom.: 0 Cov.: 33 AF XY: 0.00000298 AC XY: 2 AN XY: 672076

African (AFR) AF: 0.00 AC: 0 AN: 28634

American (AMR) AF: 0.00 AC: 0 AN: 34262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24340

East Asian (EAS) AF: 0.00 AC: 0 AN: 32920

South Asian (SAS) AF: 0.00 AC: 0 AN: 77096

European-Finnish (FIN) AF: 0.0000300 AC: 1 AN: 33354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.00000374 AC: 4 AN: 1070492

Other (OTH) AF: 0.00 AC: 0 AN: 56796

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Mucopolysaccharidosis type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		3.0
GERP RS		3.6
PromoterAI		-0.44	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1264013707; hg19: chr4-981031;