rs187110381

Variant names:

• chr4-989390-C-T
• rs187110381
• NM_022042.4:c.1549G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-989390-C-T
• chr4-989390-C-A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022042.4(SLC26A1):​c.1549G>A​(p.Gly517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,569,488 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 35)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: SLC26A1 NM_022042.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0560
• Publications: 2 publications found

Genes affected

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]

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]

IDUA Gene-Disease associations (from GenCC):

• mucopolysaccharidosis type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Scheie syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Hurler syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Hurler-Scheie syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044092834).
• BP6: Variant 4-989390-C-T is Benign according to our data. Variant chr4-989390-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022042.4. 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
	SLC26A1	NM_022042.4	MANE Select	c.1549G>A	p.Gly517Arg	missense	Exon 3 of 3	NP_071325.2
	IDUA	NM_000203.5	MANE Select	c.299+1441C>T		intron	N/A	NP_000194.2	P35475-1
	SLC26A1	NM_213613.4		c.1549G>A	p.Gly517Arg	missense	Exon 4 of 4	NP_998778.1	Q9H2B4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.1549G>A	p.Gly517Arg	missense	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1
	SLC26A1	ENST00000361661.6	TSL:1	c.1549G>A	p.Gly517Arg	missense	Exon 4 of 4	ENSP00000354721.2	Q9H2B4-1
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.299+1441C>T		intron	N/A	ENSP00000425081.2	P35475-1

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 564 AN: 152262 Hom.: 3 Cov.: 35

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000909 AC: 158 AN: 173892 AF XY: 0.000728

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.000866

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000284

Gnomad OTH exome AF: 0.000211

GnomAD4 exome AF: 0.000348 AC: 493 AN: 1417108 Hom.: 2 Cov.: 72 AF XY: 0.000294 AC XY: 206 AN XY: 700984

African (AFR) AF: 0.0128 AC: 413 AN: 32328

American (AMR) AF: 0.000817 AC: 31 AN: 37962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25354

East Asian (EAS) AF: 0.00 AC: 0 AN: 36930

South Asian (SAS) AF: 0.000172 AC: 14 AN: 81284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49040

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000826 AC: 9 AN: 1089772

Other (OTH) AF: 0.000443 AC: 26 AN: 58722

GnomAD4 genome AF: 0.00371 AC: 565 AN: 152380 Hom.: 3 Cov.: 35 AF XY: 0.00366 AC XY: 273 AN XY: 74514

African (AFR) AF: 0.0131 AC: 545 AN: 41586

American (AMR) AF: 0.000849 AC: 13 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000921 Hom.: 0

Bravo AF: 0.00390

ESP6500AA AF: 0.00906 AC: 39

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000867 AC: 102

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	SLC26A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	12
DANN	Uncertain	0.97
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.056
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.14
Sift	Benign	0.20	T
Sift4G	Benign	0.44	T
Polyphen		0.54	P
Vest4		0.10
MutPred		0.38		Gain of solvent accessibility (P = 0.0306)
MVP		0.83
MPC		0.17
ClinPred		0.0027	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.56
Mutation Taster		=100/0	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: rs187110381; hg19: chr4-983178;