4-989824-C-T

Variant names:

• chr4-989824-C-T
• rs73219719
• NM_022042.4:c.1115G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022042.4(SLC26A1):​c.1115G>A​(p.Arg372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,580,354 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R372L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0097 (21 hom., cov: 35)
  • Exomes 𝑓: 0.011 (135 hom.)
• Consequence: SLC26A1 NM_022042.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0440
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052942634).
• BP6: Variant 4-989824-C-T is Benign according to our data. Variant chr4-989824-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 376863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00971 (1480/152368) while in subpopulation AMR AF = 0.0278 (426/15310). AF 95% confidence interval is 0.0256. There are 21 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A1	NM_022042.4	MANE Select	c.1115G>A	p.Arg372His	missense	Exon 3 of 3	NP_071325.2
	IDUA	NM_000203.5	MANE Select	c.299+1875C>T		intron	N/A	NP_000194.2
	SLC26A1	NM_213613.4		c.1115G>A	p.Arg372His	missense	Exon 4 of 4	NP_998778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A1	ENST00000398516.3	TSL:1 MANE Select	c.1115G>A	p.Arg372His	missense	Exon 3 of 3	ENSP00000381528.2
	SLC26A1	ENST00000361661.6	TSL:1	c.1115G>A	p.Arg372His	missense	Exon 4 of 4	ENSP00000354721.2
	IDUA	ENST00000514224.2	TSL:2 MANE Select	c.299+1875C>T		intron	N/A	ENSP00000425081.2

Frequencies

GnomAD3 genomes AF: 0.00972 AC: 1480 AN: 152250 Hom.: 21 Cov.: 35

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0209

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0146 AC: 2818 AN: 192628 AF XY: 0.0127

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.0495

Gnomad ASJ exome AF: 0.00359

Gnomad EAS exome AF: 0.0000686

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0106 AC: 15188 AN: 1427986 Hom.: 135 Cov.: 71 AF XY: 0.0103 AC XY: 7280 AN XY: 707202

African (AFR) AF: 0.00179 AC: 59 AN: 32920

American (AMR) AF: 0.0459 AC: 1819 AN: 39662

Ashkenazi Jewish (ASJ) AF: 0.00423 AC: 108 AN: 25506

East Asian (EAS) AF: 0.00 AC: 0 AN: 38052

South Asian (SAS) AF: 0.00364 AC: 298 AN: 81760

European-Finnish (FIN) AF: 0.0227 AC: 1119 AN: 49334

Middle Eastern (MID) AF: 0.00251 AC: 14 AN: 5582

European-Non Finnish (NFE) AF: 0.0103 AC: 11237 AN: 1096072

Other (OTH) AF: 0.00904 AC: 534 AN: 59098

GnomAD4 genome AF: 0.00971 AC: 1480 AN: 152368 Hom.: 21 Cov.: 35 AF XY: 0.00988 AC XY: 736 AN XY: 74512

African (AFR) AF: 0.00171 AC: 71 AN: 41582

American (AMR) AF: 0.0278 AC: 426 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.000577 AC: 3 AN: 5196

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4832

European-Finnish (FIN) AF: 0.0209 AC: 222 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0104 AC: 708 AN: 68026

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00884 Hom.: 12

Bravo AF: 0.0106

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00163 AC: 7

ESP6500EA AF: 0.00866 AC: 73

ExAC AF: 0.00995 AC: 1181

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Nephrolithiasis, calcium oxalate (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0053	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.044
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.088	T
Sift4G	Uncertain	0.018	D
Polyphen		0.24	B
Vest4		0.11
MPC		0.18
ClinPred		0.0051	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs73219719; hg19: chr4-983612; COSMIC: COSV56101715; COSMIC: COSV56101715;