rs869320710

Positions:

chr6-42178398-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_001384910.1(GUCA1A):c.320T>C(p.Ile107Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GUCA1A
NM_001384910.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.01

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_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001384910.1

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

PP5

Variant 6-42178398-T-C is Pathogenic according to our data. Variant chr6-42178398-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225233.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr6-42178398-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GUCA1A	NM_001384910.1 linkuse as main transcript	c.320T>C	p.Ile107Thr	missense_variant	2/4	ENST00000372958.2
GUCA1ANB-GUCA1A	NM_001319061.2 linkuse as main transcript	c.320T>C	p.Ile107Thr	missense_variant	4/6
GUCA1ANB-GUCA1A	NM_000409.5 linkuse as main transcript	c.320T>C	p.Ile107Thr	missense_variant	4/6
GUCA1ANB-GUCA1A	NM_001319062.2 linkuse as main transcript	c.320T>C	p.Ile107Thr	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCA1A	ENST00000372958.2 linkuse as main transcript	c.320T>C	p.Ile107Thr	missense_variant	2/4	1	NM_001384910.1	P1
GUCA1A	ENST00000679182.1 linkuse as main transcript	c.101T>C	p.Ile34Thr	missense_variant	1/3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251388

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135876

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone dystrophy 3

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 13, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Jun 05, 2020	This variant is interpreted as likely pathogenic for Cone-rod dystrophy 14, autosomal dominant. The following ACMG Tag(s) were applied: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium (PM2); Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (PM1); Multiple lines of computational evidence support a deleterious effect on the gene or gene product (PP3); Well-established functional studies show a deleterious effect (PS3 downgraded to supporting). -

Cone-rod dystrophy 14

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 12, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

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. Experimental studies have shown that this missense change affects GUCA1A function (PMID: 26358777). 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 225233). This missense change has been observed in individual(s) with GUCA1A-related conditions (PMID: 24024198). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 107 of the GUCA1A protein (p.Ile107Thr). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

.;D;D;D

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;.;.;T

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

4.8

.;H;H;H

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.7

.;D;D;D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

.;D;D;D

Vest4

0.97

MutPred

0.71

.;Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);

MVP

0.92

MPC

0.96

ClinPred

1.0

GERP RS

4.6

Varity_R

0.91

gMVP

0.90

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