chr4-155713561-G-A

Variant names:

• chr4-155713561-G-A
• rs751701114
• NM_001130682.3:c.1550G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001130682.3(GUCY1A1):​c.1550G>A​(p.Cys517Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000024 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GUCY1A1 NM_001130682.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.97
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 4-155713561-G-A is Pathogenic according to our data. Variant chr4-155713561-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 559597.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A1	NM_001130682.3	MANE Select	c.1550G>A	p.Cys517Tyr	missense	Exon 7 of 10	NP_001124154.1
	GUCY1A1	NM_000856.6		c.1550G>A	p.Cys517Tyr	missense	Exon 8 of 11	NP_000847.2
	GUCY1A1	NM_001130683.4		c.1550G>A	p.Cys517Tyr	missense	Exon 7 of 10	NP_001124155.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCY1A1	ENST00000506455.6	TSL:1 MANE Select	c.1550G>A	p.Cys517Tyr	missense	Exon 7 of 10	ENSP00000424361.1
	GUCY1A1	ENST00000296518.11	TSL:1	c.1550G>A	p.Cys517Tyr	missense	Exon 7 of 10	ENSP00000296518.7
	GUCY1A1	ENST00000511108.5	TSL:1	c.1550G>A	p.Cys517Tyr	missense	Exon 8 of 11	ENSP00000421493.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249946 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000240 AC: 35 AN: 1461070 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 726668

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111376

Other (OTH) AF: 0.0000331 AC: 2 AN: 60348

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

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

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.85	D
PhyloP100		10
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.5	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.56		Loss of helix (P = 0.2022)
MVP		0.99
MPC		0.56
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.94
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs751701114; hg19: chr4-156634713;