4-989390-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:3
• Conservation: PhyloP100: 0.0560

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 445364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A1	NM_022042.4	c.1549G>A	p.Gly517Arg	missense_variant	3/3	ENST00000398516.3
IDUA	NM_000203.5	c.299+1441C>T		intron_variant		ENST00000514224.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A1	ENST00000398516.3	c.1549G>A	p.Gly517Arg	missense_variant	3/3	1	NM_022042.4	P1
IDUA	ENST00000514224.2	c.299+1441C>T		intron_variant		2	NM_000203.5	P1

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

GnomAD3 exomes AF: 0.000909 AC: 158 AN: 173892 Hom.: 0 AF XY: 0.000728 AC XY: 68 AN XY: 93366

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 SAS exome AF: 0.0000815

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

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000817

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000172

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000826

Gnomad4 OTH exome AF: 0.000443

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

Gnomad4 AFR AF: 0.0131

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000594 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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

SLC26A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.14
Sift	Benign	0.20	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.54	P;P
Vest4		0.10
MutPred		0.38		Gain of solvent accessibility (P = 0.0306);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs187110381; hg19: chr4-983178;