rs587777320

Variant names:

• chr4-155711252-G-A
• rs587777320
• NM_001130682.3:c.1086+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-155711252-G-A
• chr4-155711252-G-C
• chr4-155711252-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001130682.3(GUCY1A1):​c.1086+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GUCY1A1 NM_001130682.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.56
• Publications: 1 publications found

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]

GUCY1A1 Gene-Disease associations (from GenCC):

• Moyamoya disease with early-onset achalasia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.34249878 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -39, new splice context is: cgaGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-155711252-G-A is Pathogenic according to our data. Variant chr4-155711252-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 127094.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY1A1	NM_001130682.3	c.1086+1G>A		splice_donor_variant, intron_variant	Intron 6 of 9	ENST00000506455.6	NP_001124154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1A1	ENST00000506455.6	c.1086+1G>A		splice_donor_variant, intron_variant	Intron 6 of 9	1	NM_001130682.3	ENSP00000424361.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1298656 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 652086

African (AFR) AF: 0.00 AC: 0 AN: 30234

American (AMR) AF: 0.00 AC: 0 AN: 43988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24936

East Asian (EAS) AF: 0.00 AC: 0 AN: 38722

South Asian (SAS) AF: 0.00 AC: 0 AN: 82224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5456

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 965196

Other (OTH) AF: 0.00 AC: 0 AN: 54716

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Moyamoya disease with early-onset achalasia Pathogenic:1

Mar 06, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		5.6
GERP RS		5.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777320; hg19: chr4-156632404;