rs201905280

chr7-107674189-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM5 PP3 BP4_Strong

The NM_000441.2(SLC26A4):c.441G>A(p.Met147Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000244 in 1,614,126 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M147T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 9.44

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000441.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107674188-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.04811126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.441G>A	p.Met147Ile	missense_variant	5/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.441G>A	p.Met147Ile	missense_variant	5/21		NM_000441.2	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000565 AC: 142 AN: 251466 Hom.: 1 AF XY: 0.000559 AC XY: 76 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000234 AC: 342 AN: 1461862 Hom.: 2 Cov.: 31 AF XY: 0.000230 AC XY: 167 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00410

Gnomad4 NFE exome AF: 0.0000818

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74452

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000511 AC: 62

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	Identified in a patient with unilateral hearing loss and ipsilateral enlarged vestibular aqueduct in the literature (Jonard et al., 2010), but no second variant was identified; Identified in a patient with congenital hypothyroidism without hearing loss and in multiple patients with congenital hypothyroidism whose hearing status was not reported in the published literature (Fu et al., 2016; Makretskaya et al., 2018); however, a second variant was not identified and one case also had a homozygous variant in another gene; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27771369, 30245029, 26886089, 20621367, 30240412, 16570074, 20128824) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 12, 2016

The p.Met147Ile variant in SLC26A4 has been reported in 1 individual with unilat eral hearing loss and enlargement of the vestibular aqueduct (EVA) who did not h ave a second SLC26A4 variant (Jonard 2010). This variant has also been identifie d in 0.5% (35/6614) of Finnish chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs201905280). Although this variant has been seen in the general population, its frequency is not high enough to rul e out a pathogenic role. Computational prediction tools and conservation analyse s suggest that the p.Met147Ile variant may impact the protein, though this infor mation is not predictive enough to determine pathogenicity. Two additional varia nts at this position (p.Met147Val and p.Met147Thr) have also previously been rep orted in individuals with hearing loss and EVA. The p.Met147Val variant has been reported in at least 5 individuals with hearing loss and EVA all of whom were c ompound heterozygous for a second pathogenic SLC26A4 variant, and functional stu dies suggest that protein function may be altered (Park 2005, Albert 2006, Yoon 2008, Ishihara 2010, Huang 2011). The p.Met147Thr variant has been observed in a t least 3 homozygous individuals with hearing loss and segregated with hearing l oss in 1 family (Albert 2006, Rebeh 2010). In summary, the clinical significance of the p.Met147Ile variant is uncertain. -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.048	T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0030	D;.
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.87		Loss of catalytic residue at M147 (P = 0.1231);Loss of catalytic residue at M147 (P = 0.1231);
MVP		0.95
MPC		0.076
ClinPred		0.19	T
GERP RS		5.4
Varity_R		0.95
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201905280; hg19: chr7-107314634;