rs55701254

Variant names:

• chr7-107701083-T-A
• rs55701254
• NM_000441.2:c.1708-18T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BA1 BP7

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA4432923/MONDO:0010134/005

• 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:12
• Conservation: PhyloP100: 2.07
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1708-18T>A		intron	N/A	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.1708-18T>A		intron	N/A	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1708-18T>A		intron	N/A	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1630-18T>A		intron	N/A	ENSP00000558759.1

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

GnomAD2 exomes AF: 0.0256 AC: 6412 AN: 250804 AF XY: 0.0249

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 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

African (AFR) AF: 0.00451 AC: 140 AN: 31068

American (AMR) AF: 0.0178 AC: 791 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 422 AN: 25398

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.00875 AC: 732 AN: 83684

European-Finnish (FIN) AF: 0.0560 AC: 2982 AN: 53264

Middle Eastern (MID) AF: 0.0203 AC: 112 AN: 5512

European-Non Finnish (NFE) AF: 0.0329 AC: 32853 AN: 999452

Other (OTH) AF: 0.0260 AC: 1461 AN: 56286

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

African (AFR) AF: 0.00561 AC: 233 AN: 41568

American (AMR) AF: 0.0241 AC: 369 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00787 AC: 38 AN: 4828

European-Finnish (FIN) AF: 0.0569 AC: 604 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0325 AC: 2210 AN: 68008

Other (OTH) AF: 0.0232 AC: 49 AN: 2108

Alfa AF: 0.0260 Hom.: 15

Bravo AF: 0.0213

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Pendred syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.75
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55701254; hg19: chr7-107341528;