4-991150-G-T

Variant names:

• chr4-991150-G-T
• rs139024319
• NM_022042.4:c.554C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_022042.4(SLC26A1):​c.554C>A​(p.Thr185Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000214 in 1,400,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T185M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC26A1 NM_022042.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76
• 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, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Hurler syndrome

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

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-991150-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242374.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A1	NM_022042.4	c.554C>A	p.Thr185Lys	missense_variant	Exon 2 of 3	ENST00000398516.3	NP_071325.2
IDUA	NM_000203.5	c.299+3201G>T		intron_variant	Intron 2 of 13	ENST00000514224.2	NP_000194.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A1	ENST00000398516.3	c.554C>A	p.Thr185Lys	missense_variant	Exon 2 of 3	1	NM_022042.4	ENSP00000381528.2
IDUA	ENST00000514224.2	c.299+3201G>T		intron_variant	Intron 2 of 13	2	NM_000203.5	ENSP00000425081.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1400092 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 687962

African (AFR) AF: 0.00 AC: 0 AN: 32296

American (AMR) AF: 0.00 AC: 0 AN: 40110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39076

South Asian (SAS) AF: 0.00 AC: 0 AN: 76392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4840

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1077992

Other (OTH) AF: 0.00 AC: 0 AN: 57694

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;.;D;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	.;T;.;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
PhyloP100		6.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.3	D;.;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;D;D
Vest4		0.90
MutPred		0.71		Gain of ubiquitination at T185 (P = 0.0289);Gain of ubiquitination at T185 (P = 0.0289);Gain of ubiquitination at T185 (P = 0.0289);Gain of ubiquitination at T185 (P = 0.0289);
MVP		0.98
MPC		0.60
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.97
Mutation Taster		=13/87	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: rs139024319; hg19: chr4-984938;