rs111033244

Variant names:

• chr7-107690125-A-G
• rs111033244
• NM_000441.2:c.1151A>G
• SLC26A4 p.Glu384Gly

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1151A>G​(p.Glu384Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000352 in 1,577,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002548016: The most pronounced variant effect results in complete loss of Pendrin induced chloride and iodide transport (Scott_2000) and complete retention of Pendrin in the endoplasmic reticulum (ER) as a major mechanism for Pendred syndrome (Rotman-Pikielny_2002)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E384Q) has been classified as Likely pathogenic. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.7957
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 8.26
• Publications: 27 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, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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

ENSG00000300331 (HGNC:):

ACMG classification

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

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002548016: The most pronounced variant effect results in complete loss of Pendrin induced chloride and iodide transport (Scott_2000) and complete retention of Pendrin in the endoplasmic reticulum (ER) as a major mechanism for Pendred syndrome (Rotman-Pikielny_2002).; SCV000060080: Functional studies have shown that the p.Glu384Gly variant protein confers no iodide and chloride transport activity (Scott 2000 PMID: 10861298, Choi 2009 PMID: 19204907).; SCV000616879: "Published functional studies demonstrate a damaging effect due to aberrant protein processing, with retention of pendrin in the endoplasmic reticulum and absence of proper pendrin assembly at the cell membrane as well as impaired protein glycosylation (PMID: 10861298, 18310264, 12354788)"; SCV000964907: Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 12354788, 18310264, 22116358).; SCV004225732: PS3; SCV002767671: Functional studies showed the mutant protein was retained in the endoplasmic reticulum in human COS7 cells (PMID:12354788). The iodide and chloride uptake was lost in Xenopus oocytes containing the mutant cRNA. (PMID:10861298).; SCV000916171: Functional studies have shown that the p.Glu384Gly variant protein is consistently located in the intracellular region rather than the plasma membrane and shows decreased Cl-/HCO3- exchange activity (Rotman-Pikielny et al. 2002; Yoon et al. 2008) and an almost complete loss of pendrin-induced iodide and chloride transport activity compared to wild type (Scott et al. 2000; Choi et al. 2009).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000441.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107690124-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3384109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-107690125-A-G is Pathogenic according to our data. Variant chr7-107690125-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.1151A>G	p.Glu384Gly	missense splice_region	Exon 10 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1151A>G	p.Glu384Gly	missense splice_region	Exon 10 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1151A>G	p.Glu384Gly	missense splice_region	Exon 9 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1151A>G	p.Glu384Gly	missense splice_region	Exon 10 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 251090 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000373 AC: 532 AN: 1425244 Hom.: 0 Cov.: 27 AF XY: 0.000360 AC XY: 256 AN XY: 711362

African (AFR) AF: 0.0000306 AC: 1 AN: 32698

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 85536

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000480 AC: 518 AN: 1078686

Other (OTH) AF: 0.000152 AC: 9 AN: 59118

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74328

African (AFR) AF: 0.0000724 AC: 3 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000452 Hom.: 0

Bravo AF: 0.000140

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Pendred syndrome (6)
4	-	-	Autosomal recessive nonsyndromic hearing loss 4 (4)
4	-	-	not provided (4)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Rare genetic deafness (1)
1	-	-	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.97
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.80
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs111033244;

hg19: chr7-107330570;