6-42173624-T-C

Position:

• chr6-42173624-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384910.1(GUCA1A):​c.11T>C​(p.Val4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

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]

GUCA1ANB-GUCA1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093519).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GUCA1A	NM_001384910.1	c.11T>C	p.Val4Ala	missense_variant	1/4	ENST00000372958.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.11T>C	p.Val4Ala	missense_variant	3/6
GUCA1ANB-GUCA1A	NM_000409.5	c.11T>C	p.Val4Ala	missense_variant	3/6
GUCA1ANB-GUCA1A	NM_001319062.2	c.11T>C	p.Val4Ala	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GUCA1A	ENST00000372958.2	c.11T>C	p.Val4Ala	missense_variant	1/4	1	NM_001384910.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 11, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with GUCA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4 of the GUCA1A protein (p.Val4Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.54
DEOGEN2	Benign	0.12	.;T;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.54	.;.;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.48	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.46	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.0050	.;B;B;B
Vest4		0.12, 0.072, 0.075
MutPred		0.13		Loss of stability (P = 0.0892);Loss of stability (P = 0.0892);Loss of stability (P = 0.0892);Loss of stability (P = 0.0892);
MVP		0.59
MPC		0.32
ClinPred		0.11	T
GERP RS		5.9
Varity_R		0.072
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-42141362;