4-987916-G-C

Position:

• chr4-987916-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000203.5(IDUA):​c.266G>C​(p.Arg89Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.66

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IDUA	NM_000203.5	c.266G>C	p.Arg89Pro	missense_variant	2/14	ENST00000514224.2	NP_000194.2
SLC26A1	NM_022042.4	c.*917C>G		3_prime_UTR_variant	3/3	ENST00000398516.3	NP_071325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.266G>C	p.Arg89Pro	missense_variant	2/14	2	NM_000203.5	ENSP00000425081	P1
SLC26A1	ENST00000398516.3	c.*917C>G		3_prime_UTR_variant	3/3	1	NM_022042.4	ENSP00000381528	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.80		Loss of MoRF binding (P = 0.0071);
MVP		1.0
MPC		0.92
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.97
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs121965029; hg19: chr4-981704;