rs869320710

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_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. 13/22 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:4U:1

Conservation

PhyloP100: 8.01

Publications

7 publications found

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:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

GUCA1ANB-GUCA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_001384910.1

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: 0.22619 (below the threshold of 3.09). GenCC associations: The gene is linked to cone dystrophy 3, cone-rod dystrophy 14, hereditary macular dystrophy, cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy.

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 VariationId is 225233.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 2 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 4 of 6		NP_000400.2	P43080
GUCA1ANB-GUCA1A	NM_001319061.2 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 4 of 6		NP_001305990.1	P43080
GUCA1ANB-GUCA1A	NM_001319062.2 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 3 of 5		NP_001305991.1	P43080B2R9P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 2 of 4	1	NM_001384910.1	ENSP00000362049.1		P43080
GUCA1ANB-GUCA1A	ENST00000654459.1 link	c.320T>C	p.Ile107Thr	missense_variant	Exon 3 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251388

AF XY:

0.00

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cone dystrophy 3

Pathogenic:2

Jun 05, 2020

SIB Swiss Institute of Bioinformatics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

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). -

Sep 13, 2021

MGZ Medical Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cone-rod dystrophy 14

Pathogenic:1

Apr 12, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Retinal dystrophy

Pathogenic:1

Jan 01, 2020

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

May 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). This variant is present in population databases (no rsID available, gnomAD 0.004%). 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). -

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

(source)

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

PhyloP100

8.0

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

PromoterAI

0.021

Neutral

(source)

Varity_R

0.91

gMVP

0.90

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over