rs727503430

Variant names:

• chr7-107704386-G-A
• rs727503430
• NM_000441.2:c.2089+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-107704386-G-A
• chr7-107704386-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.2089+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000798 in 1,253,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000054 (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:10
• Conservation: PhyloP100: 7.13
• Publications: 5 publications found

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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.1, offset of 28, new splice context is: cctGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 7-107704386-G-A is Pathogenic according to our data. Variant chr7-107704386-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 165263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2089+1G>A		splice_donor_variant, intron_variant	Intron 18 of 20	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2089+1G>A		splice_donor_variant, intron_variant	Intron 18 of 20		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.376+1G>A		splice_donor_variant, intron_variant	Intron 3 of 5	5
SLC26A4	ENST00000644846.1	n.744+2329G>A		intron_variant	Intron 7 of 9			ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000135 AC: 3 AN: 222764 AF XY: 0.00000836

Gnomad AFR exome AF: 0.000139

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000545 AC: 6 AN: 1101766 Hom.: 0 Cov.: 15 AF XY: 0.00000355 AC XY: 2 AN XY: 562718

African (AFR) AF: 0.0000751 AC: 2 AN: 26630

American (AMR) AF: 0.00 AC: 0 AN: 43202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23392

East Asian (EAS) AF: 0.00 AC: 0 AN: 37952

South Asian (SAS) AF: 0.00 AC: 0 AN: 77326

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5098

European-Non Finnish (NFE) AF: 0.00000380 AC: 3 AN: 788542

Other (OTH) AF: 0.0000208 AC: 1 AN: 47970

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74264

African (AFR) AF: 0.0000725 AC: 3 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000521 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000832 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:4

Jul 15, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC26A4 c.2089+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 222764 control chromosomes (gnomAD). The variant, c.2089+1G>A, has been reported in the literature in homozygous and compound heterozygous state in individuals affected with hearing loss, with- or without the thyroid signs that are characteristic for Pendred Syndrome (e.g. Albert_2006, Ladsous_2014, Sheppard_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Sep 25, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 18 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs727503430, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 2422447, 15355436). ClinVar contains an entry for this variant (Variation ID: 165263). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

May 03, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2089+1G>A variant in the SLC26A4 gene has been reported previously in the presence of another SLC26A4 variant, in individuals with Pendred syndrome, exhibiting sensorineural hearing loss, vestibular aqueductal enlargement and both with and without thyroid involvement (Blons et al., 2004; Banghova et al., 2008; Ladsous et al., 2014). This splice site variant destroys the canonical splice donor site in intron 18. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2089+1G>A variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2089+1G>A as a pathogenic variant. -

Rare genetic deafness Pathogenic:1

Apr 11, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 2089+1G>A variant in SLC26A4 has been previously identified in two individua ls with Pendred syndrome and segregated with disease in an affected sibling of one of these individuals (Blons 2004, Banghova 2008). This variant was absent fr om large population studies. The variant occurs in the invariant region (+1/2) o f the 5? splice consensus sequence and is predicted to cause altered splicing le ading to an abnormal or absent protein. In summary, this variant meets our crite ria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.1
GERP RS		5.4
Mutation Taster		=0/100	disease causing (ClinVar)

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		0.42		Position offset: 40
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727503430; hg19: chr7-107344831;