6-42178410-A-C

Variant names:

• chr6-42178410-A-C
• rs1554186385
• NM_001384910.1:c.332A>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_001384910.1(GUCA1A):​c.332A>C​(p.Glu111Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E111V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

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: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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001384910.1
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42178410-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 962836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.979
• PP5: Variant 6-42178410-A-C is Pathogenic according to our data. Variant chr6-42178410-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438157.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384910.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1A	NM_001384910.1	MANE Select	c.332A>C	p.Glu111Ala	missense	Exon 2 of 4	NP_001371839.1
	GUCA1ANB-GUCA1A	NM_000409.5		c.332A>C	p.Glu111Ala	missense	Exon 4 of 6	NP_000400.2
	GUCA1ANB-GUCA1A	NM_001319061.2		c.332A>C	p.Glu111Ala	missense	Exon 4 of 6	NP_001305990.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GUCA1A	ENST00000372958.2	TSL:1 MANE Select	c.332A>C	p.Glu111Ala	missense	Exon 2 of 4	ENSP00000362049.1
	GUCA1ANB-GUCA1A	ENST00000654459.1		c.332A>C	p.Glu111Ala	missense	Exon 3 of 5	ENSP00000499539.1
	GUCA1A	ENST00000679182.1		c.113A>C	p.Glu38Ala	missense	Exon 1 of 3	ENSP00000504837.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.92		Loss of stability (P = 0.2664)
MVP		0.91
MPC		0.83
ClinPred		1.0	D
GERP RS		3.4
PromoterAI		-0.054	Neutral
Varity_R		0.95
gMVP		0.92
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554186385; hg19: chr6-42146148;