chr7-107696048-C-T

Position:

• chr7-107696048-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000441.2(SLC26A4):​c.1544+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,454,764 control chromosomes in the GnomAD database, including 17 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 0.00061 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (17 hom.)
• Consequence: SLC26A4 NM_000441.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.381

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-107696048-C-T is Benign according to our data. Variant chr7-107696048-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165255.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr7-107696048-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1544+9C>T		intron_variant		ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1544+9C>T		intron_variant			NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 152008 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00187 AC: 470 AN: 251208 Hom.: 4 AF XY: 0.00247 AC XY: 336 AN XY: 135762

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00117 AC: 1519 AN: 1302638 Hom.: 17 Cov.: 20 AF XY: 0.00158 AC XY: 1037 AN XY: 656582

Gnomad4 AFR exome AF: 0.000231

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.0000514

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.000320

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000834 AC XY: 62 AN XY: 74360

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000459

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000540 Hom.: 1

Bravo AF: 0.000348

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous c.1544+9C>T variant in SLC26A4 has been identified in 3 individuals with Pendred syndrome (PMID: 21704276, 25214170, 21961810), but has also been identified in >1% of South Asian chromosomes and 2 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive Pendred syndrome. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2015	1544+9C>T in Intron 13 of SLC26A4: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 1.3% (213/16512) of South Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368970459 ). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2018	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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.5
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs368970459; hg19: chr7-107336493;