chr7-30964126-G-A
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000823.4(GHRHR):c.57+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000284 in 1,547,964 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
Consequence
NM_000823.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHRHR | NM_000823.4 | c.57+1G>A | splice_donor_variant | ENST00000326139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHRHR | ENST00000326139.7 | c.57+1G>A | splice_donor_variant | 1 | NM_000823.4 | P1 | |||
GHRHR | ENST00000466427.1 | n.285-4708G>A | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000196 AC: 3AN: 153272Hom.: 0 AF XY: 0.0000371 AC XY: 3AN XY: 80882
GnomAD4 exome AF: 0.0000244 AC: 34AN: 1395738Hom.: 0 Cov.: 32 AF XY: 0.0000232 AC XY: 16AN XY: 688510
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2019 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 31902114, 30860584, 29571594, 30959475, 28456063, 10822217, 24272598, 27552668, 25761575, 10084571, 24398366, 24057284, 23052699) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2021 | 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: 15990). Disruption of this splice site has been observed in individuals with growth hormone deficiency (PMID: 10084571, 23052699). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 1 of the GHRHR 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 GHRHR are known to be pathogenic (PMID: 12444890, 16355809). - |
Isolated growth hormone deficiency, type 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at