rs397516421

Variant names:

• chr7-107701101-G-A
• rs397516421
• NM_000441.2:c.1708G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-107701101-G-A
• chr7-107701101-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM3_Strong PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.1708G>A variant in SLC26A4 is a missense variant predicted to cause the substitution of valine by isoleucine at amino acid 570 (p.Val570Ile). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computations predictor REVEL gives a score of 0.547, which is neither above nor below the thresholds predicting a damaging or benign impact on SLC26A4 function. This variant is located at the first nucleotide of the exon and is heavily conserved in UCSC. Splice prediction analysis using MaxEntScan suggests an impact on splicing from the loss of the 3' consensus splice sequence (PP3). The c.1708G>A (p.Val570Ile) variant in SLC26A4 has also been detected in 3 different patients with hearing loss and the variant was found in trans with the pathogenic variant p.Leu117Phe.This variant has been detected in at least 3 individuals with Pendred syndrome. All of these individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant confirmed in trans (3 PM3 points, PMID:34170635, SCV000060111.6) (PM3_Strong). At least two probands with this variant displayed features of sensorineural hearing loss and enlarged vestibular aqueduct, a phenotype specific for Pendred syndrome (PMID:34170635, SCV000060111.6) (PP4). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss VCEP: PM3_Strong, PM2_Supporting, PP3, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 10/31/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA132675/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Likely pathogenic reviewed by expert panel P:8 U:2
• Conservation: PhyloP100: 7.68
• Publications: 4 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

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM3: 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.1708G>A	p.Val570Ile	missense splice_region	Exon 16 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.1708G>A	p.Val570Ile	missense splice_region	Exon 16 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1708G>A	p.Val570Ile	missense splice_region	Exon 15 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1630G>A	p.Val544Ile	missense splice_region	Exon 15 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251016 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000300 AC: 43 AN: 1434714 Hom.: 0 Cov.: 26 AF XY: 0.0000419 AC XY: 30 AN XY: 715664

African (AFR) AF: 0.00 AC: 0 AN: 32938

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 85690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1087426

Other (OTH) AF: 0.0000505 AC: 3 AN: 59412

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	1	-	Pendred syndrome (3)
1	-	-	Autosomal recessive nonsyndromic hearing loss 4 (1)
-	1	-	not specified (1)
1	-	-	Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)
1	-	-	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.55
Sift	Benign	0.082	T
Sift4G	Benign	0.14	T
Polyphen		0.97	D
Vest4		0.62
MutPred		0.50		Gain of catalytic residue at V570 (P = 0.0182)
MVP		0.99
MPC		0.076
ClinPred		0.42	T
GERP RS		5.7
Varity_R		0.35
gMVP		0.62
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.080		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: rs397516421; hg19: chr7-107341546;