rs80338849

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received 13 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2_SupportingPP5_Strong

The NM_000441.2(SLC26A4):c.1001+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000282 (AC=454) in the gnomAD database across 1,612,484 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000331. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:30O:2

Conservation

PhyloP100: 6.97

Publications

42 publications found

Variant links:

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Pendred syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Natera, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC26A4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000441.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 points.

PVS1

Splice site frameshift, NMD predicted, LoF disease mechanism — very strong (PVS1); Splice donor variant predicted to cause a frameshift, triggering NMD. Loss of function is a known disease mechanism for this gene.

PM2

Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000331 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.00131) — PM2 supporting.

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (30/30 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1001+1G>A		splice_donor intron	N/A	NP_000432.1	O43511-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SLC26A4	ENST00000644269.2	MANE Select	c.1001+1G>A	splice_donor intron	N/A	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000888701.1		c.1001+1G>A	splice_donor intron	N/A	ENSP00000558760.1	O43511-1
SLC26A4	ENST00000888700.1		c.1001+1G>A	splice_donor intron	N/A	ENSP00000558759.1	A0ACI8QA40

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000196

AC:

AN:

250282

AF XY:

0.000214

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000288

AC:

420

AN:

1460326

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

726558

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33424

American (AMR)

AF:

0.0000671

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000361

AC:

401

AN:

1110772

Other (OTH)

AF:

0.000215

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000223

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.000242

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.000339

AC:

158

AN:

466006

Hom.:

Local populations

ESP6500 (Exome Variant Server)

AF:

0.000461

AC:

AN:

13006

show subpopulations

European American

AF:

0.000581

AC:

AN:

8600

African American

AF:

0.000227

AC:

AN:

4406

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000570

AC:

AN:

122390

Hom.:

UK10K

AF:

0.000264

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.000560

AC:

AN:

3574

ALSPAC

AF:

0.00

AC:

AN:

3854

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

6 / 11110AF: 0.000540054

10 / 17608AF: 0.000567924

BipEx

(Bipolar disorder (including schizoaffective))

9 / 28420AF: 0.000316678

9 / 28844AF: 0.000312023

SCHEMA

(Schizophrenia)

30 / 121782AF: 0.000246342

35 / 190612AF: 0.000183619

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Pendred syndrome (10)

Autosomal recessive nonsyndromic hearing loss 4 (6)

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)

SLC26A4-related disorder (3)

Monogenic hearing loss (1)

Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

PhyloP100

7.0

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-9.8

(source)

GPN-Star score

9.8

(source)

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.78

Position offset: 39

DS_DL_spliceai

0.99

Position offset: -1

Pangolin (max)

Pathogenic

0.86

(source)

Pangolin gain

0.64

Position offset: 39

Pangolin loss

0.86

Position offset: -1

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over