7-107672245-G-T

Variant names:

• chr7-107672245-G-T
• rs111033199
• NM_000441.2:c.412G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS4 PP1_Moderate PS3_Supporting PP4 PP3 PM3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The p.Val138Phe variant in SLC26A4 has been detected in over 4 patients with Pendred syndrome or hearing loss with enlarged vestibular aqueducts who harbored a pathogenic or suspected pathogenic variant in trans with p.Val138Phe (PM3_VS; PMID:17503324, 15689455, 20597900, 18285825, 23965030, 24224479, 21551164, 23273637, 12788906, 16570074). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID:25999548, 23336812, 26683941). The p.Val138Phe variant in SLC26A4 has been reported to segregate with hearing loss in at least 2 family members (PP1_M; PMID:12788906). The allele frequency of the p.Val138Phe variant in the SLC26A4 gene is 0.03% (38/126540) of European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_P). Computational prediction tools and conservation analysis suggest that the p.Val138Phe variant may impact the protein (PP3). At least one patient with a variant in this gene displayed features of EVA and/or Mondini malformation which are consistent with Pendred syndrome (PP4; PMID:12788906, 23273637). A functional study performed in HeLa and human embryonic kidney cell lines demonstrated that pendrin harboring the p.Val138Phe variant did not localize to the cell membrane. However, there was no effect on iodide efflux (PS3_P; PMID:11932316). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome/EVA based on the ACMG/AMP criteria applied: PM3_VS, PS4, PP1_M, PM2_Supporting, PP3, PP4, PS3_P. LINK:https://erepo.genome.network/evrepo/ui/classification/CA253312/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:22
• Conservation: PhyloP100: 4.29
• Publications: 40 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.412G>T	p.Val138Phe	missense	Exon 4 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.412G>T	p.Val138Phe	missense	Exon 4 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.412G>T	p.Val138Phe	missense	Exon 3 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.412G>T	p.Val138Phe	missense	Exon 4 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151896 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251236 AF XY: 0.000162

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000268 AC: 379 AN: 1412074 Hom.: 1 Cov.: 24 AF XY: 0.000257 AC XY: 181 AN XY: 705508

African (AFR) AF: 0.0000308 AC: 1 AN: 32492

American (AMR) AF: 0.0000448 AC: 2 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25842

East Asian (EAS) AF: 0.00 AC: 0 AN: 39392

South Asian (SAS) AF: 0.00 AC: 0 AN: 85204

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.000332 AC: 354 AN: 1066940

Other (OTH) AF: 0.000222 AC: 13 AN: 58634

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152014 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74322

African (AFR) AF: 0.0000964 AC: 4 AN: 41486

American (AMR) AF: 0.000131 AC: 2 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67940

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000278 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	-	-	Pendred syndrome (8)
5	-	-	not provided (5)
3	-	-	Autosomal recessive nonsyndromic hearing loss 4 (3)
2	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)
2	-	-	SLC26A4-related disorder (2)
1	-	-	Hearing impairment (1)
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.99
MPC		0.012
ClinPred		0.25	T
GERP RS		5.1
Varity_R		0.83
gMVP		0.93
Mutation Taster		=17/83	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: rs111033199; hg19: chr7-107312690;