rs1553914737

Variant names:

• chr4-987085-A-C
• rs1553914737
• NM_000203.5:c.1A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-987085-A-C
• chr4-987085-A-G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000203.5(IDUA):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: IDUA NM_000203.5 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: -1.98
• Publications: 2 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]

DGKQ (HGNC:2856): (diacylglycerol kinase theta) The protein encoded by this gene contains three cysteine-rich domains, a proline-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. It is localized in the speckle domains of the nucleus, and mediates the regeneration of phosphatidylinositol (PI) from diacylglycerol in the PI-cycle during cell signal transduction. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 67 pathogenic variants. Next in-frame start position is after 133 codons. Genomic position: 1000893. Lost 0.202 part of the original CDS.
• PS1: Another start lost variant in NM_000203.5 (IDUA) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-987085-A-C is Pathogenic according to our data. Variant chr4-987085-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 550458.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	NM_000203.5	MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+4043T>G		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.89A>C		non_coding_transcript_exon	Exon 1 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+4043T>G		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152028 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2110

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	12
DANN	Benign	0.66
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.33	T
PhyloP100		-2.0
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.61
MutPred		0.98		Loss of glycosylation at P6 (P = 0.0238)
MVP		0.87
ClinPred		0.54	D
GERP RS		-2.0
PromoterAI		0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.63
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1553914737; hg19: chr4-980873;