chr4-155708248-AAG-A

Variant names:

• chr4-155708248-AAG-A
• rs781020381
• NM_001130682.3:c.334_335delGA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PVS1 PP5 BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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, Likely_pathogenic=1, Pathogenic=1}.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 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 GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. This position FAILED quality control check. 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
GUCY1A1	NM_001130682.3	c.334_335delGA	p.Glu112ArgfsTer3	frameshift_variant	Exon 5 of 10	ENST00000506455.6	NP_001124154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1A1	ENST00000506455.6	c.334_335delGA	p.Glu112ArgfsTer3	frameshift_variant	Exon 5 of 10	1	NM_001130682.3	ENSP00000424361.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152212 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000683 AC: 17 AN: 248772 AF XY: 0.0000668

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 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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31334

Gnomad4 AMR exome AF: 0.000591 AC: 26 AN: 44022

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25318

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39158

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 83542

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53274

Gnomad4 NFE exome AF: 0.00000590 AC: 6 AN: 1016902

Gnomad4 Remaining exome AF: 0.0000882 AC: 5 AN: 56672

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74492

Gnomad4 AFR AF: 0.0000481 AC: 0.0000480931 AN: 0.0000480931

Gnomad4 AMR AF: 0.000523 AC: 0.000522944 AN: 0.000522944

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000294023 AN: 0.0000294023

Gnomad4 OTH AF: 0.000473 AC: 0.00047259 AN: 0.00047259

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Moyamoya disease with early-onset achalasia Pathogenic:2

Jan 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs781020381; hg19: chr4-156629400;