chr4-155697037-A-C

Position:

• chr4-155697037-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130682.3(GUCY1A1):​c.170A>C​(p.Glu57Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00744 in 1,613,220 control chromosomes in the GnomAD database, including 757 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (405 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (352 hom.)
• Consequence: GUCY1A1 NM_001130682.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.96

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014294982).
• BP6: Variant 4-155697037-A-C is Benign according to our data. Variant chr4-155697037-A-C is described in ClinVar as [Benign]. Clinvar id is 1600192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCY1A1	NM_001130682.3	c.170A>C	p.Glu57Ala	missense_variant	3/10	ENST00000506455.6	NP_001124154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCY1A1	ENST00000506455.6	c.170A>C	p.Glu57Ala	missense_variant	3/10	1	NM_001130682.3	ENSP00000424361	P1

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5982 AN: 152162 Hom.: 404 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0105 AC: 2636 AN: 251136 Hom.: 179 AF XY: 0.00780 AC XY: 1059 AN XY: 135700

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.00843

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00539

GnomAD4 exome AF: 0.00411 AC: 6002 AN: 1460940 Hom.: 352 Cov.: 30 AF XY: 0.00357 AC XY: 2594 AN XY: 726866

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00929

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000228

Gnomad4 OTH exome AF: 0.00952

GnomAD4 genome AF: 0.0394 AC: 6000 AN: 152280 Hom.: 405 Cov.: 33 AF XY: 0.0380 AC XY: 2830 AN XY: 74458

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.00667 Hom.: 112

Bravo AF: 0.0452

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.135 AC: 593

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0126 AC: 1534

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

GUCY1A1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.099	T;T;T;.;T;T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.68	.;T;.;T;.;.;T
MetaRNN	Benign	0.0014	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.79	N;.;N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;.;T;T;T;T;T
Sift4G	Benign	0.70	T;T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;B;B;B
Vest4		0.024
MPC		0.079
ClinPred		0.0012	T
GERP RS		1.7
Varity_R		0.038
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs61736997; hg19: chr4-156618189;