rs55701254

chr7-107701083-T-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000441.2(SLC26A4):c.1708-18T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,490,604 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.024 (74 hom., cov: 32)
  • Exomes 𝑓: 0.030 (682 hom.)
• Consequence: SLC26A4 NM_000441.2 intron
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 7-107701083-T-A is Benign according to our data. Variant chr7-107701083-T-A is described in ClinVar as [Benign]. Clinvar id is 256155.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-107701083-T-A is described in Lovd as [Benign]. Variant chr7-107701083-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0236 (3588/152270) while in subpopulation NFE AF= 0.0325 (2210/68008). AF 95% confidence interval is 0.0314. There are 74 homozygotes in gnomad4. There are 1756 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 74 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.1708-18T>A		intron_variant		ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1708-18T>A		intron_variant			NM_000441.2	P1
SLC26A4	ENST00000644846.1	c.419-18T>A		intron_variant, NMD_transcript_variant
SLC26A4	ENST00000480841.5	n.557-18T>A		intron_variant, non_coding_transcript_variant		3
SLC26A4	ENST00000492030.2	n.91-744T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3584 AN: 152152 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0242

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.0256 AC: 6412 AN: 250804 Hom.: 126 AF XY: 0.0249 AC XY: 3378 AN XY: 135584

Gnomad AFR exome AF: 0.00551

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00830

Gnomad FIN exome AF: 0.0574

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0295 AC: 39493 AN: 1338334 Hom.: 682 Cov.: 21 AF XY: 0.0287 AC XY: 19299 AN XY: 673334

Gnomad4 AFR exome AF: 0.00451

Gnomad4 AMR exome AF: 0.0178

Gnomad4 ASJ exome AF: 0.0166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00875

Gnomad4 FIN exome AF: 0.0560

Gnomad4 NFE exome AF: 0.0329

Gnomad4 OTH exome AF: 0.0260

GnomAD4 genome AF: 0.0236 AC: 3588 AN: 152270 Hom.: 74 Cov.: 32 AF XY: 0.0236 AC XY: 1756 AN XY: 74456

Gnomad4 AFR AF: 0.00561

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0569

Gnomad4 NFE AF: 0.0325

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0260 Hom.: 15

Bravo AF: 0.0213

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2018	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23280318) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Pendred syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Mar 18, 2020	The filtering allele frequency (the lower threshold of the 95% CI of 1456/25104) of the c.1708-18T>A variant in the SLC26A4 gene is 5.55% for European (Finnish) chromosomes by gnomAD v2.1.1, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). This silent variant in SLC26A4 is not predicted by the computational prediction analysis using MaxEntScan to impact splicing (BP7, BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP7, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs55701254; hg19: chr7-107341528;