chr4-155708248-AAG-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_001130682.3(GUCY1A1):c.334_335delGA(p.Glu112ArgfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000332 in 1,508,022 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001130682.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000683 AC: 17AN: 248772Hom.: 0 AF XY: 0.0000668 AC XY: 9AN XY: 134718
GnomAD4 exome AF: 0.0000273 AC: 37AN: 1355692Hom.: 0 AF XY: 0.0000279 AC XY: 19AN XY: 680640
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74492
ClinVar
Submissions by phenotype
Moyamoya disease with early-onset achalasia Pathogenic:1
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not specified Pathogenic:1
The c.334_335delGA (p.E112Rfs*3) alteration, located in exon 5 (coding exon 3) of the GUCY1A3 gene, consists of a deletion of 2 nucleotides from position 334 to 335, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from the Genome Aggregation Database (gnomAD) database, the GUCY1A3 c.334_335delGA alteration was observed in 0.007% (17/248,772) of total alleles studied, with a frequency of 0.04% (13/33,908) in the Latino subpopulation. This alteration was confirmed compound heterozygous with c.1550G>A, p.C517Y, in a 3 year old female patient with a diagnosis of Moyamoya disease (Wallace, 2016). Exome sequencing was performed on the patient, her unaffected parents, and two unaffected sisters. The patient had two strokes, dysphagia, hypertension, and a brain MRI showing evidence of bilateral middle cerebral artery infarcts and generalized volume loss. Based on the available evidence, this alteration is classified as pathogenic. -
Moyamoya disease 1 Pathogenic:1
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See cases Uncertain:1
ACMG classification criteria: PS4, PM2, PM3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at