rs28939086

Variant names:

• chr7-107690220-A-C
• rs28939086
• NM_000441.2:c.1246A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-107690220-A-C
• chr7-107690220-A-G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1246A>C​(p.Thr416Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000218 in 1,602,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000514664: Published functional studies demonstrate that presence of T416P is associated with decreased or absent pendrin-induced transport of chloride, iodide, and bicarbonate in Xenopus oocytes (Scott et al., 2000" and additional evidence is available in ClinVar. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:3
• Conservation: PhyloP100: 6.32
• Publications: 79 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: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000514664: Published functional studies demonstrate that presence of T416P is associated with decreased or absent pendrin-induced transport of chloride, iodide, and bicarbonate in Xenopus oocytes (Scott et al., 2000; Yoon et al., 2008); SCV000939229: Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 10861298, 12354788, 18310264).; SCV001244767: Additionally, functional analysis has shown that the altered pendrin fails to localise to the cell membrane and is retained in the intracellular region (Yoon, JS. et al. (2008)).; SCV001809840: Well-established functional studies show damaging effect on the gene or gene product. No iodide transport activity was observed with the pendrin products encoded by p.Thr416Pro (PMID: 10861298), since they are retained in the endoplasmic reticulum (ER) (PMID: 12354788); SCV000916172: Functional studies demonstrated that the p.Thr416Pro variant protein is retained in the endoplasmic reticulum and does not reach the plasma membrane as wild type, and the variant protein showed almost complete loss of iodide transport capacity (Rotman-Pikielny et al. 2002; Yoon et al. 2008).; SCV006161950: "In multiple assays testing SLC26A4 function, this variant showed functionally abnormal results" (Scott, 2000; Rotman-Pikielny, 2002).
• PM1: In a hotspot region, there are 23 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000441.2
• 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, 0.956
• PP5: Variant 7-107690220-A-C is Pathogenic according to our data. Variant chr7-107690220-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4818.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.1246A>C	p.Thr416Pro	missense	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.1246A>C	p.Thr416Pro	missense	Exon 10 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1246A>C	p.Thr416Pro	missense	Exon 9 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1246A>C	p.Thr416Pro	missense	Exon 10 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

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: 0.000323

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000203 AC: 51 AN: 250802 AF XY: 0.000214

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000221 AC: 320 AN: 1450680 Hom.: 0 Cov.: 28 AF XY: 0.000205 AC XY: 148 AN XY: 722506

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.000112 AC: 5 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.00 AC: 0 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000280 AC: 309 AN: 1101864

Other (OTH) AF: 0.000100 AC: 6 AN: 60004

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74316

African (AFR) AF: 0.000169 AC: 7 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15260

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: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000450 Hom.: 0

Bravo AF: 0.000140

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Pendred syndrome (6)
4	-	-	Autosomal recessive nonsyndromic hearing loss 4 (5)
1	-	-	Inborn genetic diseases (1)
1	-	-	Monogenic hearing loss (1)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
1	-	-	Rare genetic deafness (1)
1	-	-	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.77
MVP		0.98
MPC		0.074
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.98
gMVP		0.95
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs28939086; hg19: chr7-107330665;