4-987896-C-G

Variant names:

• chr4-987896-C-G
• rs148775298
• NM_000203.5:c.246C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 2P and 18B. PM1 BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000203.5(IDUA):​c.246C>G​(p.His82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,609,594 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H82P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (31 hom.)
• Consequence: IDUA NM_000203.5 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts B:7 O:4
• Conservation: PhyloP100: -1.99
• Publications: 30 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: Benign. The variant received -16 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_000203.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.09837252).
• BP6: Variant 4-987896-C-G is Benign according to our data. Variant chr4-987896-C-G is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 92637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00375 (572/152358) while in subpopulation NFE AF = 0.00611 (416/68034). AF 95% confidence interval is 0.00563. There are 1 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 AR gene

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.246C>G	p.His82Gln	missense	Exon 2 of 14	NP_000194.2	P35475-1
	SLC26A1	NM_022042.4	MANE Select	c.*937G>C		3_prime_UTR	Exon 3 of 3	NP_071325.2
	SLC26A1	NM_213613.4		c.*937G>C		3_prime_UTR	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.246C>G	p.His82Gln	missense	Exon 2 of 14	ENSP00000425081.2	P35475-1
	IDUA	ENST00000247933.9	TSL:1	c.246C>G	p.His82Gln	missense	Exon 2 of 14	ENSP00000247933.4	P35475-1
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.*937G>C		3_prime_UTR	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 571 AN: 152240 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00862

GnomAD2 exomes AF: 0.00293 AC: 689 AN: 235294 AF XY: 0.00279

Gnomad AFR exome AF: 0.000804

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00178

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00363

GnomAD4 exome AF: 0.00522 AC: 7601 AN: 1457236 Hom.: 31 Cov.: 30 AF XY: 0.00492 AC XY: 3563 AN XY: 724634

African (AFR) AF: 0.00102 AC: 34 AN: 33402

American (AMR) AF: 0.00354 AC: 157 AN: 44340

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85600

European-Finnish (FIN) AF: 0.00151 AC: 78 AN: 51694

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5742

European-Non Finnish (NFE) AF: 0.00626 AC: 6952 AN: 1110636

Other (OTH) AF: 0.00613 AC: 369 AN: 60238

GnomAD4 genome AF: 0.00375 AC: 572 AN: 152358 Hom.: 1 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74514

African (AFR) AF: 0.00103 AC: 43 AN: 41580

American (AMR) AF: 0.00477 AC: 73 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00611 AC: 416 AN: 68034

Other (OTH) AF: 0.00853 AC: 18 AN: 2110

Alfa AF: 0.00358 Hom.: 1

Bravo AF: 0.00394

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00734 AC: 63

ExAC AF: 0.00254 AC: 306

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Hurler syndrome (2)
-	-	1	Inborn genetic diseases (1)
-	-	-	Mucopolysaccharidosis type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	5.6
DANN	Benign	0.87
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		-2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.48
Sift	Benign	0.12	T
Sift4G	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.93
MutPred		0.57		Loss of glycosylation at K86 (P = 0.0815)
MVP		0.92
MPC		0.73
ClinPred		0.045	T
GERP RS		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.48
gMVP		0.55
Mutation Taster		=88/12	polymorphism

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: rs148775298; hg19: chr4-981684; COSMIC: COSV99926634; COSMIC: COSV99926634;