NM_001130682.3:c.1045C>G

Variant names:

• chr4-155711210-C-G
• rs587777321
• NM_001130682.3:c.1045C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001130682.3(GUCY1A1):​c.1045C>G​(p.Arg349Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GUCY1A1 NM_001130682.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

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.1045C>G	p.Arg349Gly	missense	Exon 6 of 10	NP_001124154.1	Q02108-1
	GUCY1A1	NM_000856.6		c.1045C>G	p.Arg349Gly	missense	Exon 7 of 11	NP_000847.2	Q02108-1
	GUCY1A1	NM_001130683.4		c.1045C>G	p.Arg349Gly	missense	Exon 6 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.1045C>G	p.Arg349Gly	missense	Exon 6 of 10	ENSP00000424361.1	Q02108-1
	GUCY1A1	ENST00000296518.11	TSL:1	c.1045C>G	p.Arg349Gly	missense	Exon 6 of 10	ENSP00000296518.7	Q02108-1
	GUCY1A1	ENST00000511108.5	TSL:1	c.1045C>G	p.Arg349Gly	missense	Exon 7 of 11	ENSP00000421493.1	Q02108-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457206 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 725234

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107826

Other (OTH) AF: 0.00 AC: 0 AN: 60234

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.55	D
PhyloP100		1.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.63
Sift	Benign	0.43	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.74		Loss of MoRF binding (P = 0.0408)
MVP		0.94
MPC		0.49
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.66
gMVP		0.88
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587777321; hg19: chr4-156632362;