Genetic Variant NM_001384910.1:c.567C>A (chr6-42179364-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001384910.1(GUCA1A):c.567C>A(p.Asp189Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D189D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GUCA1A
NM_001384910.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.98

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:

ENSG00000290147 (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]

ENSG00000290147 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028991759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 4 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 6 of 6		NP_000400.2	P43080
GUCA1ANB-GUCA1A	NM_001319061.2 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 6 of 6		NP_001305990.1	P43080
GUCA1ANB-GUCA1A	NM_001319062.2 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 5 of 5		NP_001305991.1	P43080B2R9P6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 4 of 4	1	NM_001384910.1	ENSP00000362049.1		P43080
ENSG00000290147	ENST00000654459.1 link	c.567C>A	p.Asp189Glu	missense_variant	Exon 5 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458922

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725418

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0010

DANN

Benign

0.20

DEOGEN2

Benign

0.13

.;T;T;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.30

T;.;.;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.029

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

.;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.14

.;N;N;N

REVEL

Benign

0.036

Sift

Benign

1.0

.;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;B

Vest4

0.079

MutPred

0.20

.;Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);Gain of loop (P = 0.1081);

MVP

0.16

MPC

0.22

ClinPred

0.035

GERP RS

-8.7

Varity_R

0.029

gMVP

0.21

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over