chr7-107661656-C-A

Position:

• chr7-107661656-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000441.2(SLC26A4):​c.15C>A​(p.Gly5Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,567,138 control chromosomes in the GnomAD database, including 15 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 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (7 hom.)
• Consequence: SLC26A4 NM_000441.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:10
• Conservation: PhyloP100: 0.365

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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 7-107661656-C-A is Benign according to our data. Variant chr7-107661656-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43515.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=6}. Variant chr7-107661656-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.365 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00617 (940/152384) while in subpopulation AFR AF= 0.0213 (886/41596). AF 95% confidence interval is 0.0201. There are 8 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.15C>A	p.Gly5Gly	synonymous_variant	2/21	ENST00000644269.2	NP_000432.1
SLC26A4-AS1	NR_028137.1	n.143G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.15C>A	p.Gly5Gly	synonymous_variant	2/21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.00617 AC: 939 AN: 152266 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00145 AC: 256 AN: 176868 Hom.: 5 AF XY: 0.00108 AC XY: 105 AN XY: 96938

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.000968

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000400

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000900

Gnomad OTH exome AF: 0.000833

GnomAD4 exome AF: 0.000688 AC: 973 AN: 1414754 Hom.: 7 Cov.: 30 AF XY: 0.000619 AC XY: 434 AN XY: 700636

Gnomad4 AFR exome AF: 0.0239

Gnomad4 AMR exome AF: 0.00113

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000246

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000494

Gnomad4 OTH exome AF: 0.00134

GnomAD4 genome AF: 0.00617 AC: 940 AN: 152384 Hom.: 8 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74532

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.00202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.00676

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Uncertain:1 Benign:3

Uncertain significance, 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. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 29, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2019	- -
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	Aug 01, 2024	SLC26A4: BP4, BP7, BS1, BS2; SLC26A4-AS1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2019	This variant is associated with the following publications: (PMID: 29739340, 23280318) -

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

Uncertain significance, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 24, 2012	Gly5Gly in exon 2 of SLC26A4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, has been identified in 1.4% (54/3922) of African American chromosomes from a broad population by the NHLBI Exome sequencing proje ct (http://evs.gs.washington.edu/EVS/). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.92

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: rs7811324; hg19: chr7-107302101;