4-987148-C-T

Variant names:

• chr4-987148-C-T
• rs1001972534
• NM_000203.5:c.64C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000203.5(IDUA):​c.64C>T​(p.Pro22Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000791 in 1,263,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P22A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.691
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18893793).

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.64C>T	p.Pro22Ser	missense	Exon 1 of 14	NP_000194.2
	SLC26A1	NM_134425.4		c.576+3980G>A		intron	N/A	NP_602297.1
	IDUA	NR_110313.1		n.152C>T		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.64C>T	p.Pro22Ser	missense	Exon 1 of 14	ENSP00000425081.2
	IDUA	ENST00000247933.9	TSL:1	c.64C>T	p.Pro22Ser	missense	Exon 1 of 14	ENSP00000247933.4
	SLC26A1	ENST00000398520.6	TSL:1	c.576+3980G>A		intron	N/A	ENSP00000381532.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD4 exome AF: 7.91e-7 AC: 1 AN: 1263616 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 620816

African (AFR) AF: 0.00 AC: 0 AN: 24966

American (AMR) AF: 0.00 AC: 0 AN: 19318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20316

East Asian (EAS) AF: 0.00 AC: 0 AN: 27360

South Asian (SAS) AF: 0.00 AC: 0 AN: 61862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3632

European-Non Finnish (NFE) AF: 9.78e-7 AC: 1 AN: 1022852

Other (OTH) AF: 0.00 AC: 0 AN: 51978

GnomAD4 genome Cov.: 36

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Hurler syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	3.3
DANN	Benign	0.86
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.69
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.55	N
REVEL	Pathogenic	0.69
Sift	Benign	0.44	T
Sift4G	Benign	0.43	T
Polyphen		0.0030	B
Vest4		0.64
MutPred		0.24		Loss of catalytic residue at P21 (P = 0.0179)
MVP		0.61
MPC		0.19
ClinPred		0.033	T
GERP RS		-0.49
PromoterAI		0.026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.020
gMVP		0.46
Mutation Taster		=27/73	disease causing

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: rs1001972534; hg19: chr4-980936;