rs75832628

Variant names:

• chr4-155708284-A-G
• rs75832628
• NM_001130682.3:c.366A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001130682.3(GUCY1A1):​c.366A>G​(p.Ala122Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000802 in 1,537,122 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: GUCY1A1 NM_001130682.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.859
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-155708284-A-G is Benign according to our data. Variant chr4-155708284-A-G is described in ClinVar as Benign. ClinVar VariationId is 776027.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.859 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00403 (614/152344) while in subpopulation AFR AF = 0.0138 (572/41580). AF 95% confidence interval is 0.0128. There are 5 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.366A>G	p.Ala122Ala	synonymous	Exon 5 of 10	NP_001124154.1	Q02108-1
	GUCY1A1	NM_000856.6		c.366A>G	p.Ala122Ala	synonymous	Exon 6 of 11	NP_000847.2	Q02108-1
	GUCY1A1	NM_001130683.4		c.366A>G	p.Ala122Ala	synonymous	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.366A>G	p.Ala122Ala	synonymous	Exon 5 of 10	ENSP00000424361.1	Q02108-1
	GUCY1A1	ENST00000296518.11	TSL:1	c.366A>G	p.Ala122Ala	synonymous	Exon 5 of 10	ENSP00000296518.7	Q02108-1
	GUCY1A1	ENST00000511108.5	TSL:1	c.366A>G	p.Ala122Ala	synonymous	Exon 6 of 11	ENSP00000421493.1	Q02108-1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152226 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00103 AC: 257 AN: 250078 AF XY: 0.000813

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000788

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000990

GnomAD4 exome AF: 0.000447 AC: 619 AN: 1384778 Hom.: 4 Cov.: 22 AF XY: 0.000408 AC XY: 283 AN XY: 693534

African (AFR) AF: 0.0152 AC: 486 AN: 31910

American (AMR) AF: 0.000834 AC: 37 AN: 44380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25554

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.0000830 AC: 7 AN: 84374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.000891 AC: 5 AN: 5610

European-Non Finnish (NFE) AF: 0.0000182 AC: 19 AN: 1042636

Other (OTH) AF: 0.00113 AC: 65 AN: 57720

GnomAD4 genome AF: 0.00403 AC: 614 AN: 152344 Hom.: 5 Cov.: 32 AF XY: 0.00409 AC XY: 305 AN XY: 74488

African (AFR) AF: 0.0138 AC: 572 AN: 41580

American (AMR) AF: 0.00203 AC: 31 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00451

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.6
DANN	Benign	0.65
PhyloP100		0.86
Mutation Taster		=100/0	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: rs75832628; hg19: chr4-156629436;