4-155696895-A-G

Variant names:

• chr4-155696895-A-G
• rs6854098
• NM_001130682.3:c.28A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001130682.3(GUCY1A1):​c.28A>G​(p.Lys10Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,457,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. K10Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GUCY1A1 NM_001130682.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• 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: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33081353).

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.28A>G	p.Lys10Glu	missense	Exon 3 of 10	NP_001124154.1	Q02108-1
	GUCY1A1	NM_000856.6		c.28A>G	p.Lys10Glu	missense	Exon 4 of 11	NP_000847.2	Q02108-1
	GUCY1A1	NM_001130683.4		c.28A>G	p.Lys10Glu	missense	Exon 3 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.28A>G	p.Lys10Glu	missense	Exon 3 of 10	ENSP00000424361.1	Q02108-1
	GUCY1A1	ENST00000296518.11	TSL:1	c.28A>G	p.Lys10Glu	missense	Exon 3 of 10	ENSP00000296518.7	Q02108-1
	GUCY1A1	ENST00000511108.5	TSL:1	c.28A>G	p.Lys10Glu	missense	Exon 4 of 11	ENSP00000421493.1	Q02108-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250838 AF XY: 0.0000148

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1457106 Hom.: 0 Cov.: 30 AF XY: 0.00000552 AC XY: 4 AN XY: 725088

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107746

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.085	T
PhyloP100		6.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.63	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.17	T
Polyphen		0.19	B
Vest4		0.41
MutPred		0.39		Loss of sheet (P = 0.0228)
MVP		0.85
MPC		0.13
ClinPred		0.81	D
GERP RS		4.8
Varity_R		0.24
gMVP		0.61
Mutation Taster		=81/19	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: rs6854098; hg19: chr4-156618047;