rs1057516243

Positions:

• chr7-107698092-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1595G>T​(p.Ser532Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S532?) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.77

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107698090-AAG-AT is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 7-107698092-G-T is Pathogenic according to our data. Variant chr7-107698092-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1595G>T	p.Ser532Ile	missense_variant	14/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1595G>T	p.Ser532Ile	missense_variant	14/21		NM_000441.2	ENSP00000494017	P1
SLC26A4	ENST00000477350.5	n.442G>T		non_coding_transcript_exon_variant	4/5	4
SLC26A4	ENST00000480841.5	n.444G>T		non_coding_transcript_exon_variant	5/8	3
SLC26A4	ENST00000644846.1	c.308G>T	p.Ser103Ile	missense_variant, NMD_transcript_variant	4/10			ENSP00000494344

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456652 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 24, 2015	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35114279, 25372295, 24599119, 28786104, 19954013, 23185506, 30842343, LiuY2023b[Preprint], 23918157, 35982127, WuL2017[Article], 22384008, 26252218) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2022	This missense change has been observed in individuals with nonsyndromic enlarged vestibular aqueduct (PMID: 17718863, 23918157, 25372295). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 532 of the SLC26A4 protein (p.Ser532Ile). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 370114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function. This variant disrupts the p.Ser532 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17718863, 23918157, 25372295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.59	D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0040	D;.
Polyphen		0.40	B;B
Vest4		0.55
MutPred		0.83		Loss of disorder (P = 0.0012);Loss of disorder (P = 0.0012);
MVP		0.98
MPC		0.022
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057516243; hg19: chr7-107338537;