chr4-987240-C-G

Variant names:

• chr4-987240-C-G
• rs1421520718
• NM_000203.5:c.156C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000203.5(IDUA):​c.156C>G​(p.Phe52Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,361,740 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: IDUA NM_000203.5 missense, splice_region
• Scores: Splicing: ADA: 0.03485
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.729
• 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: AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IDUA	NM_000203.5	c.156C>G	p.Phe52Leu	missense_variant, splice_region_variant	Exon 1 of 14	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IDUA	ENST00000514224.2	c.156C>G	p.Phe52Leu	missense_variant, splice_region_variant	Exon 1 of 14	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000308 AC: 42 AN: 1361740 Hom.: 0 Cov.: 33 AF XY: 0.0000327 AC XY: 22 AN XY: 671898

African (AFR) AF: 0.0000350 AC: 1 AN: 28580

American (AMR) AF: 0.00 AC: 0 AN: 34246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24328

East Asian (EAS) AF: 0.00 AC: 0 AN: 32862

South Asian (SAS) AF: 0.00 AC: 0 AN: 77046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.0000383 AC: 41 AN: 1070436

Other (OTH) AF: 0.00 AC: 0 AN: 56784

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hurler syndrome Uncertain:1

Oct 11, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mucopolysaccharidosis, MPS-I-S;C0086431:Mucopolysaccharidosis, MPS-I-H/S;C0086795:Hurler syndrome Uncertain:1

Mar 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;.
PhyloP100		0.73
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.8	D;N
REVEL	Pathogenic	0.67
Sift	Benign	0.65	T;D
Sift4G	Benign	0.31	T;D
Polyphen		0.81	P;.
Vest4		0.68
MutPred		0.67		Gain of glycosylation at T56 (P = 0.0787);Gain of glycosylation at T56 (P = 0.0787);
MVP		0.98
MPC		0.69
ClinPred		0.95	D
GERP RS		1.8
PromoterAI		-0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.81
gMVP		0.81
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.035
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.020		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: rs1421520718; hg19: chr4-981028;