rs55638457

Positions:

• chr7-107701183-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000441.2(SLC26A4):​c.1790T>C​(p.Leu597Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00837 in 1,598,500 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0062 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (118 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:17
• Conservation: PhyloP100: 6.17

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 Benign. Variant got -11 ACMG points.

• PM1: In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000441.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.008705229).
• BP6: Variant 7-107701183-T-C is Benign according to our data. Variant chr7-107701183-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43525.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=7, Uncertain_significance=1}. Variant chr7-107701183-T-C is described in Lovd as [Benign]. Variant chr7-107701183-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00623 (949/152304) while in subpopulation SAS AF= 0.0282 (136/4820). AF 95% confidence interval is 0.0244. There are 7 homozygotes in gnomad4. There are 476 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1790T>C	p.Leu597Ser	missense_variant	16/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1790T>C	p.Leu597Ser	missense_variant	16/21		NM_000441.2	ENSP00000494017	P1
SLC26A4	ENST00000480841.5	n.639T>C		non_coding_transcript_exon_variant	7/8	3
SLC26A4	ENST00000644846.1	c.503T>C	p.Leu168Ser	missense_variant, NMD_transcript_variant	6/10			ENSP00000494344
SLC26A4	ENST00000492030.2	n.91-644T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 949 AN: 152186 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00813

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00833 AC: 2092 AN: 251102 Hom.: 28 AF XY: 0.00982 AC XY: 1333 AN XY: 135694

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0206

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0281

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00756

Gnomad OTH exome AF: 0.00752

GnomAD4 exome AF: 0.00860 AC: 12437 AN: 1446196 Hom.: 118 Cov.: 27 AF XY: 0.00942 AC XY: 6786 AN XY: 720586

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0294

Gnomad4 FIN exome AF: 0.000843

Gnomad4 NFE exome AF: 0.00782

Gnomad4 OTH exome AF: 0.00826

GnomAD4 genome AF: 0.00623 AC: 949 AN: 152304 Hom.: 7 Cov.: 32 AF XY: 0.00639 AC XY: 476 AN XY: 74462

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00813

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00856 Hom.: 7

Bravo AF: 0.00601

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00823 AC: 999

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.00856

EpiControl AF: 0.00794

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 24, 2014	p.Leu597Ser in exon 16 of SLC26A4: Although this variant has been reported in pa tients with Pendred syndrome and nonsyndromic hearing loss with enlarged vestibu lar aqueducts (EVA) (Campbell et al 2001, Fugazzola et al 2002, Blons 2004, Pryo r 2005), it has also been found in 2.7% (449/16590) of South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs55638457). In addition, this variant has been identified by our laboratory in many individuals, none of whom had a pathogenic variant on the second allele. I n summary, this data meets our criteria to classify this variant as benign. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SLC26A4: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pendred syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	.;T
MetaRNN	Benign	0.0087	T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.4	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D;.
Sift4G	Benign	0.072	T;.
Polyphen		1.0	D;D
Vest4		0.75
MVP		0.99
MPC		0.074
ClinPred		0.013	T
GERP RS		5.7
Varity_R		0.66
gMVP		0.71

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: rs55638457; hg19: chr7-107341628;