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

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

GUCY1A1
NM_001130682.3 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.09
Variant links:
Genes affected
GUCY1A1 (HGNC:4685): (guanylate cyclase 1 soluble subunit alpha 1) Soluble guanylate cyclases are heterodimeric proteins that catalyze the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. The protein encoded by this gene is an alpha subunit of this complex and it interacts with a beta subunit to form the guanylate cyclase enzyme, which is activated by nitric oxide. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-155708248-AAG-A is Pathogenic according to our data. Variant chr4-155708248-AAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 559598.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000273 (37/1355692) while in subpopulation AMR AF= 0.000591 (26/44022). AF 95% confidence interval is 0.000413. There are 0 homozygotes in gnomad4_exome. There are 19 alleles in male gnomad4_exome subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GUCY1A1NM_001130682.3 linkc.334_335delGA p.Glu112ArgfsTer3 frameshift_variant Exon 5 of 10 ENST00000506455.6 NP_001124154.1 Q02108-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GUCY1A1ENST00000506455.6 linkc.334_335delGA p.Glu112ArgfsTer3 frameshift_variant Exon 5 of 10 1 NM_001130682.3 ENSP00000424361.1 Q02108-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
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:
0.0000294
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000683
AC:
17
AN:
248772
Hom.:
0
AF XY:
0.0000668
AC XY:
9
AN XY:
134718
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000383
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.0000273
AC:
37
AN:
1355692
Hom.:
0
AF XY:
0.0000279
AC XY:
19
AN XY:
680640
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000591
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000590
Gnomad4 OTH exome
AF:
0.0000882
GnomAD4 genome
AF:
0.0000853
AC:
13
AN:
152330
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Moyamoya disease with early-onset achalasia Pathogenic:1
Aug 16, 2018
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not specified Pathogenic:1
May 18, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

See cases Uncertain:1
Apr 26, 2021
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PS4, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

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: rs781020381; hg19: chr4-156629400; API