rs763062791
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5
The NM_001038603.3(MARVELD2):c.1147-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000437 in 1,602,778 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001038603.3 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MARVELD2 | NM_001038603.3 | c.1147-2A>G | splice_acceptor_variant | ENST00000325631.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MARVELD2 | ENST00000325631.10 | c.1147-2A>G | splice_acceptor_variant | 1 | NM_001038603.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152272Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251142Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135764
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1450506Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3AN XY: 722322
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74394
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 49 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 25, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 04, 2021 | This variant is present in population databases (rs763062791, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with MARVELD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 505800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change affects an acceptor splice site in intron 2 of the MARVELD2 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 MARVELD2 are known to be pathogenic (PMID: 17186462). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 21, 2017 | Variant classified as Uncertain Significance - Favor Pathogenic. The c.1147-2A>G variant in MARVELD2 has not been previously reported in individuals with hearin g loss, but has been indentified in 7/18864 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs763062 761). Although this variant has been seen in the general population, its frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt occurs in the invariant region (+/- 1/2) of the splice consensus sequence and would be predicted to cause altered splicing leading to an abnormal or absent p rotein. While loss of function of the MARVELD2 gene is an established disease m echanism in autosomal recessive hearing loss, two transcripts of the MARVELD2 ge ne exist, with the second transcript (NM_001244734) lacking the exon that would be impacted by this variant. RT-PCR data from human lymphoblastoid cell lines sh ow that both transcripts are expressed in the cochlea (Riazuddin 2006), raising the possibility that this exon is not required for protein function. However, th ere is insufficient protein expression or functional data to determine this. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of this variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at