11-532760-G-C
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005343.4(HRAS):c.451-5C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,184 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005343.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.451-5C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000311189.8 | |||
HRAS | NM_176795.5 | c.*20-5C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.451-5C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_005343.4 | P1 | |||
HRAS | ENST00000417302.7 | c.*20-5C>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000809 AC: 2AN: 247162Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134320
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1459934Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 726336
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152250Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74380
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 14, 2018 | The c.451-5 C>G variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been reported in ClinVar as a likely benign variant by an outside laboratory (SCV000560905.2; Landrum et al., 2016). The c.451-5 C>G variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Nevertheless, in silico splice prediction programs are inconclusive as to whether this variant has an impact on normal gene splicing. Lastly, splice site variants have not been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014). However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. - |
Costello syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at