Genetic Variant NM_001130682.3:c.170A>C (chr4-155697037-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.96

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GUCY1A1	NM_001130682.3 link	c.170A>C	p.Glu57Ala	missense_variant	Exon 3 of 10	ENST00000506455.6	NP_001124154.1	Q02108-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1A1	ENST00000506455.6 link	c.170A>C	p.Glu57Ala	missense_variant	Exon 3 of 10	1	NM_001130682.3	ENSP00000424361.1		Q02108-1

Frequencies

GnomAD3 genomes

AF:

0.0393

AC:

5982

AN:

152162

Hom.:

404

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00357

AC XY:

2594

AN XY:

726866

show subpopulations

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.:

AF XY:

0.0380

AC XY:

2830

AN XY:

74458

show subpopulations

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:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.135

AC:

593

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0126

AC:

1534

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

GUCY1A1-related disorder

Benign:1

Aug 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.46

CADD

Benign

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

LIST_S2

Benign

0.68

.;T;.;T;.;.;T

MetaRNN

Benign

0.0014

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.26

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over