rs60284988

Variant names:

• chr7-107660756-T-C
• rs60284988
• ENST00000888701.1:c.-886T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. BS1 PS3_Supporting PM3 PP4

This summary comes from the ClinGen Evidence Repository: The c.-103T>C (NM_000441.2) variant is a substitution in the 5’ UTR of SLC26A4. Because the variant is located in the 5’ UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v4.0.0 is 0.3% (262/68066 alleles) in the European (non-Finnish) population, which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel (HL EP) for autosomal recessive hearing loss variants (BS1). This variant has been detected in 2 individuals with hearing loss and additional features of Pendred syndrome (enlarged vestibular aqueducts (EVA) and Mondini dysplasia) who were compound heterozygous for the variant and a pathogenic variant with phase confirmed in trans in one individual (PMID:19204907, 25991456). It has also been identified in two additional compound heterozygous individuals with hearing loss, one with a likely pathogenic and one with a variant of uncertain significance, though phase was not confirmed in either individual (SCV000491274.5). However, due to the allele frequency meeting BS1 criteria, PP4 and PM3 were not applied. There have been many reported heterozygous observations in individuals with EVA/Pendred syndrome (PMID:17503324, 23208854, 23965030, 25991456). Functional studies imply that the variant occurs in a binding site that is a major transcriptional regulatory element of SLC26A4 and is necessary for FOXI1-induced transcriptional activation of SLC26A4 (PMID:25910213, 17503324; PS3_Supporting). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: BS1, PS3_P (ClinGen Hearing Loss VCEP specifications version 2; 01/17/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA253314/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SLC26A4 ENST00000888701.1 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:7 B:3
• Conservation: PhyloP100: 3.81
• Publications: 13 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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000888701.1. 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-AS1	NR_028137.1		n.198-550A>G		intron	N/A
	SLC26A4	NM_000441.2	MANE Select	c.-103T>C		upstream_gene	N/A	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000888701.1		c.-886T>C		5_prime_UTR	Exon 1 of 20	ENSP00000558760.1
	SLC26A4-AS1	ENST00000658036.1		n.1141A>G		non_coding_transcript_exon	Exon 2 of 2
	SLC26A4-AS1	ENST00000689362.1		n.1077A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00201 AC: 306 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00191

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 48 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 38

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 36

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.00201 AC: 306 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74486

African (AFR) AF: 0.000168 AC: 7 AN: 41586

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000257 Hom.: 0

Bravo AF: 0.00177

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	2	not provided (6)
1	2	-	Pendred syndrome (3)
-	1	1	not specified (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	Hearing impairment (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Benign	0.82
PhyloP100		3.8
PromoterAI		0.029	Neutral
Mutation Taster		=118/182	disease causing

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: rs60284988; hg19: chr7-107301201;