7-107674944-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.601-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000274 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 splice_acceptor
NM_000441.2 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.19
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06999573 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.1, offset of 21, new splice context is: tgatatttggtggcttgcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-107674944-G-A is Pathogenic according to our data. Variant chr7-107674944-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 446452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107674944-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.601-1G>A | splice_acceptor_variant | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.601-1G>A | splice_acceptor_variant | NM_000441.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 genomes
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30
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727192
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GnomAD4 genome Cov.: 30
GnomAD4 genome
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30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1Other:1
Affects, no assertion criteria provided | clinical testing;in vitro | National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center | Aug 20, 2019 | in vitro experiment - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center | Jul 01, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | This sequence change affects an acceptor splice site in intron 5 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 446452). This variant is also known as IVS5-1G>A. Disruption of this splice site has been observed in individual(s) with SLC26A4-related conditions (PMID: 14508505, 25788563). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 22
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at