6-42173662-G-A

Position:

chr6-42173662-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BS1_SupportingBS2

The NM_001384910.1(GUCA1A):c.49G>A(p.Glu17Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

GUCA1A
NM_001384910.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.86

Variant links:

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

GUCA1A links:

GUCA1ANB-GUCA1A (HGNC:):

GUCA1ANB-GUCA1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.784

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00000684 (10/1461780) while in subpopulation AMR AF= 0.000134 (6/44724). AF 95% confidence interval is 0.000058. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GUCA1A	NM_001384910.1 linkuse as main transcript	c.49G>A	p.Glu17Lys	missense_variant	1/4	ENST00000372958.2
GUCA1ANB-GUCA1A	NM_001319061.2 linkuse as main transcript	c.49G>A	p.Glu17Lys	missense_variant	3/6
GUCA1ANB-GUCA1A	NM_000409.5 linkuse as main transcript	c.49G>A	p.Glu17Lys	missense_variant	3/6
GUCA1ANB-GUCA1A	NM_001319062.2 linkuse as main transcript	c.49G>A	p.Glu17Lys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCA1A	ENST00000372958.2 linkuse as main transcript	c.49G>A	p.Glu17Lys	missense_variant	1/4	1	NM_001384910.1	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251444

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461780

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 17 of the GUCA1A protein (p.Glu17Lys). This variant is present in population databases (rs778379606, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GUCA1A-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;.;T;T;T

Eigen

Uncertain

0.63

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

.;D;.;.;D

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Benign

-0.29

MutationAssessor

Pathogenic

3.7

.;.;H;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

D;.;D;D;D

REVEL

Uncertain

0.49

Sift

Benign

0.039

D;.;D;D;D

Sift4G

Uncertain

0.026

D;D;D;D;D

Polyphen

0.48

.;.;P;P;P

Vest4

0.75, 0.86, 0.93, 0.93

MutPred

0.63

Gain of methylation at E17 (P = 0.0016);.;Gain of methylation at E17 (P = 0.0016);Gain of methylation at E17 (P = 0.0016);Gain of methylation at E17 (P = 0.0016);

MVP

0.87

MPC

0.29

ClinPred

0.90

GERP RS

6.0

Varity_R

0.44

gMVP

0.81

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