chr7-107660860-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_000441.2(SLC26A4):​c.-4+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 152,188 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

SLC26A4
NM_000441.2 splice_donor_5th_base, intron

Scores

2
Splicing: ADA: 0.9985
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 3.10
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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 7-107660860-G-A is Pathogenic according to our data. Variant chr7-107660860-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165245.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.-4+5G>A splice_donor_5th_base_variant, intron_variant ENST00000644269.2
SLC26A4-AS1NR_028137.1 linkuse as main transcriptn.198-654C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.-4+5G>A splice_donor_5th_base_variant, intron_variant NM_000441.2 P1O43511-1
SLC26A4-AS1ENST00000668981.1 linkuse as main transcriptn.257+742C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000657
AC:
10
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
114
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
86
Gnomad4 AFR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.000125

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchKing Laboratory, University of WashingtonFeb 28, 2023This variant was found in compound heterozygosity with an SLC26A4 splicing variant that is known to be pathogenic, in a patient with bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no history of childhood-onset hearing loss. This variant is a single base pair substitution within the 5’ UTR that is predicted to interfere with normal splicing. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 2 heterozygotes on gnomAD. Based on compound heterozygosity with a loss-of-function variant, consistently predicted functional effect, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. -
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 17, 2014The -4+5G>A variant in SLC26A4 has been identified in one individual with hearin g loss and EVA by our laboratory (LMM unpublished data) likely in trans with an other pathogenic variant SLC26A4 variant. In addition, this variant has not bee n identified in large population studies and is located in the 5' splice region. Computational tools suggest a possible impact to splicing; though this informat ion is not predictive enough to determine pathogenicity. In summary, this varia nt is likely pathogenic. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 24, 2023- -
SLC26A4-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 17, 2024The SLC26A4 c.-4+5G>A variant is located in the 5' untranslated region. This variant is located in the 5' untranslated region and is predicted to possibly impact splicing (Alamut Visual v2.11). To our knowledge, this variant has not been reported in the literature but has been reported in ClinVar as being likely in trans to a second pathogenic variant in a patient with hearing loss and enlarged vestibular aqueduct (https://www.ncbi.nlm.nih.gov/clinvar/variation/165245/). This variant is reported in 0.24% of alleles in individuals of Latino descent, and in 2 of ~31,000 total alleles in the gnomAD database. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.51
CADD
Benign
23
DANN
Benign
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.89
SpliceAI score (max)
0.75
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.75
Position offset: -5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503425; hg19: chr7-107301305; API