rs781020381

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
• Publications: 2 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: Genomics England PanelApp, Orphanet

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 VariationId is 559598.
• 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 passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130682.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A1	NM_001130682.3	MANE Select	c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 5 of 10	NP_001124154.1	Q02108-1
	GUCY1A1	NM_000856.6		c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 6 of 11	NP_000847.2	Q02108-1
	GUCY1A1	NM_001130683.4		c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 5 of 10	NP_001124155.1	Q02108-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A1	ENST00000506455.6	TSL:1 MANE Select	c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 5 of 10	ENSP00000424361.1	Q02108-1
	GUCY1A1	ENST00000296518.11	TSL:1	c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 5 of 10	ENSP00000296518.7	Q02108-1
	GUCY1A1	ENST00000511108.5	TSL:1	c.334_335delGA	p.Glu112ArgfsTer3	frameshift	Exon 6 of 11	ENSP00000421493.1	Q02108-1

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

African (AFR) AF: 0.00 AC: 0 AN: 31334

American (AMR) AF: 0.000591 AC: 26 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25318

East Asian (EAS) AF: 0.00 AC: 0 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 83542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5470

European-Non Finnish (NFE) AF: 0.00000590 AC: 6 AN: 1016902

Other (OTH) 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

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000166

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Moyamoya disease with early-onset achalasia (2)
1	-	-	Moyamoya disease 1 (1)
1	-	-	not specified (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1
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

Other links and lift over

dbSNP: rs781020381; hg19: chr4-156629400;