NM_000441.2:c.765+3A>T

Variant names:

• chr7-107675112-A-T
• rs483353048
• NM_000441.2:c.765+3A>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.765+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002229414: Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID:23336812)." and additional evidence is available in ClinVar. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 splice_region, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.82
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002229414: Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 23336812).; SCV003928982: Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site and one predicts it weakens the 5' donor site. At least two publications report experimental evidence that this variant indeed affects mRNA splicing, causing the skipping of exon 6, which is predicted to result in an in-frame deletion of the exon.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-107675112-A-T is Pathogenic according to our data. Variant chr7-107675112-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1454511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.765+3A>T		splice_region intron	N/A	NP_000432.1	O43511-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	ENST00000644269.2	MANE Select	c.765+3A>T		splice_region intron	N/A	ENSP00000494017.1	O43511-1
	SLC26A4	ENST00000888701.1		c.765+3A>T		splice_region intron	N/A	ENSP00000558760.1
	SLC26A4	ENST00000888700.1		c.765+3A>T		splice_region intron	N/A	ENSP00000558759.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461280 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726968

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111496

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Pendred syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	12
DANN	Benign	0.89
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs483353048; hg19: chr7-107315557;