rs111033243

Variant names:

• chr7-107689112-T-C
• rs111033243
• NM_000441.2:c.1061T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS3

This summary comes from the ClinGen Evidence Repository: The c.1061T>C variant in SLC26A4 is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 354 (p.Phe354Ser). The filtering allele frequency (95% CI) in gnomAD v.2.1.1 was 0.1102% (153/251206 alleles, 6 homozygotes) in Latino/Admixed American population which meets the AR threshold (≥0.07%) for BS1_P. Although the REVEL computational prediction analysis tool produced a score of 0.955, PP3 was not applied. It was observed in 3 probands with sensorineural hearing loss, however they were not scored due to the high FAF in gnomAD (PMID:26226137, 32747562, 27861301). Functional studies have shown that this variant does not affect the ability of the protein to mediate iodide and chloride transport (PMID:22116359, 31599023) meeting BS3. In summary, this variant is likely benign for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the ClinGen Hearing Loss Expert Panel: BS3, BS1_P (ClinGen Hearing Loss VCEP specifications version 2; 11/28/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA132656/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (6 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:8 B:11 O:1
• Conservation: PhyloP100: 7.17
• Publications: 20 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: Likely_benign. The variant received -5 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.1061T>C	p.Phe354Ser	missense	Exon 9 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.1061T>C	p.Phe354Ser	missense	Exon 9 of 21	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.1061T>C	p.Phe354Ser	missense	Exon 8 of 20	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.1061T>C	p.Phe354Ser	missense	Exon 9 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes AF: 0.000854 AC: 130 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000609 AC: 153 AN: 251206 AF XY: 0.000545

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000687

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.000519 AC: 759 AN: 1461670 Hom.: 6 Cov.: 31 AF XY: 0.000512 AC XY: 372 AN XY: 727136

African (AFR) AF: 0.00146 AC: 49 AN: 33466

American (AMR) AF: 0.00190 AC: 85 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00850 AC: 49 AN: 5766

European-Non Finnish (NFE) AF: 0.000429 AC: 477 AN: 1111852

Other (OTH) AF: 0.00164 AC: 99 AN: 60388

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000899 AC XY: 67 AN XY: 74486

African (AFR) AF: 0.000626 AC: 26 AN: 41566

American (AMR) AF: 0.00405 AC: 62 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68040

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000683 Hom.: 0

Bravo AF: 0.00151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	5	not provided (9)
1	1	1	Autosomal recessive nonsyndromic hearing loss 4 (4)
-	1	2	not specified (3)
-	2	1	Pendred syndrome (3)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	SLC26A4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.22	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MVP		0.99
MPC		0.074
ClinPred		0.060	T
GERP RS		5.6
Varity_R		0.95
gMVP		0.94
Mutation Taster		=32/68	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: rs111033243; hg19: chr7-107329557;