4-987183-T-C

Variant names:

• chr4-987183-T-C
• rs10794537
• NM_000203.5:c.99T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000203.5(IDUA):​c.99T>C​(p.His33His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000757 in 1,321,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 38)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 0 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: AD, AR Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP7: Synonymous conserved (PhyloP=-2.44 with no splicing effect.

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.99T>C	p.His33His	synonymous	Exon 1 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_134425.4		c.576+3945A>G		intron	N/A	NP_602297.1	Q9H2B4-2
	IDUA	NR_110313.1		n.187T>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.99T>C	p.His33His	synonymous	Exon 1 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.99T>C	p.His33His	synonymous	Exon 1 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3945A>G		intron	N/A	ENSP00000381532.2	Q9H2B4-2

Frequencies

GnomAD3 genomes Cov.: 38

GnomAD4 exome AF: 7.57e-7 AC: 1 AN: 1321296 Hom.: 0 Cov.: 42 AF XY: 0.00000154 AC XY: 1 AN XY: 651284

African (AFR) AF: 0.00 AC: 0 AN: 26630

American (AMR) AF: 0.00 AC: 0 AN: 27900

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23200

East Asian (EAS) AF: 0.00 AC: 0 AN: 28562

South Asian (SAS) AF: 0.00 AC: 0 AN: 72678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050822

Other (OTH) AF: 0.0000183 AC: 1 AN: 54706

GnomAD4 genome Cov.: 38

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		-2.4
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs10794537; hg19: chr4-980971;