chr4-989390-C-G

Variant names:

• chr4-989390-C-G
• NM_022042.4:c.1549G>C
• SLC26A1 p.Gly517Arg

Variant summary

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

The NM_022042.4(SLC26A1):​c.1549G>C​(p.Gly517Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 35)
• Consequence: SLC26A1 NM_022042.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 0 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: ClinGen, Myriad Women's Health
• Scheie syndrome

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

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

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

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=0.1622361).

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>C	p.Gly517Arg	missense	Exon 3 of 3	NP_071325.2
	IDUA	NM_000203.5	MANE Select	c.299+1441C>G		intron	N/A	NP_000194.2	P35475-1
	SLC26A1	NM_213613.4		c.1549G>C	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>C	p.Gly517Arg	missense	Exon 3 of 3	ENSP00000381528.2	Q9H2B4-1
	SLC26A1	ENST00000361661.6	TSL:1	c.1549G>C	p.Gly517Arg	missense	Exon 4 of 4	ENSP00000354721.2	Q9H2B4-1
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.299+1441C>G		intron	N/A	ENSP00000425081.2	P35475-1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 72

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0014	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	9.9
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.056
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.44	T
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr4-983178;