Genetic Variant NM_005459.4:c.451A>C (chr3-108908201-T-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005459.4(GUCA1C):c.451A>C(p.Thr151Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GUCA1C
NM_005459.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82

Variant links:

Genes affected

GUCA1C (HGNC:4680): (guanylate cyclase activator 1C) Predicted to enable calcium ion binding activity and calcium sensitive guanylate cyclase activator activity. Predicted to be involved in signal transduction. Predicted to be located in photoreceptor disc membrane. [provided by Alliance of Genome Resources, Apr 2022]

GUCA1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3153491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1C	NM_005459.4 link	c.451A>C	p.Thr151Pro	missense_variant	Exon 4 of 4	ENST00000261047.8	NP_005450.3	O95843-1
GUCA1C	NM_001363884.1 link	c.491A>C	p.Asp164Ala	missense_variant	Exon 4 of 4		NP_001350813.1
GUCA1C	XM_011513334.3 link	c.199A>C	p.Thr67Pro	missense_variant	Exon 4 of 4		XP_011511636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1C	ENST00000261047.8 link	c.451A>C	p.Thr151Pro	missense_variant	Exon 4 of 4	1	NM_005459.4	ENSP00000261047.3		O95843-1
GUCA1C	ENST00000393963.7 link	c.491A>C	p.Asp164Ala	missense_variant	Exon 4 of 4	1		ENSP00000377535.3		C9JNI2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250972

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135650

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457790

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725466

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.451A>C (p.T151P) alteration is located in exon 4 (coding exon 4) of the GUCA1C gene. This alteration results from a A to C substitution at nucleotide position 451, causing the threonine (T) at amino acid position 151 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.089

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.26

M_CAP

Benign

0.052

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.018

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.48

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.023

Polyphen

0.93

Vest4

0.36

MutPred

0.49

Loss of helix (P = 0.0237);

MVP

0.85

ClinPred

0.97

GERP RS

2.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over