6-42173654-G-C

Position:

• chr6-42173654-G-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.41G>C​(p.Ser14Thr) variant causes a missense change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. S14S) 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: 5.31

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]

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]

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=0.17917371).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.41G>C	p.Ser14Thr	missense_variant	1/4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.41G>C	p.Ser14Thr	missense_variant	3/6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.41G>C	p.Ser14Thr	missense_variant	3/6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.41G>C	p.Ser14Thr	missense_variant	2/5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.41G>C	p.Ser14Thr	missense_variant	1/4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459.1	c.41G>C	p.Ser14Thr	missense_variant	2/5			ENSP00000499539.1

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

Retinal dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.094	.;.;T;T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.042
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.66	.;T;.;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.72	.;.;N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.98	N;.;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.95	T;.;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.035	.;.;B;B;B
Vest4		0.30, 0.095, 0.10, 0.10
MutPred		0.24		Loss of phosphorylation at S14 (P = 0.0665);.;Loss of phosphorylation at S14 (P = 0.0665);Loss of phosphorylation at S14 (P = 0.0665);Loss of phosphorylation at S14 (P = 0.0665);
MVP		0.73
MPC		0.24
ClinPred		0.68	D
GERP RS		5.1
Varity_R		0.19
gMVP		0.51

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

Other links and lift over

dbSNP: rs1767870135; hg19: chr6-42141392;