3-108916159-A-G

Position:

• chr3-108916159-A-G

Variant summary

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

The NM_005459.4(GUCA1C):​c.410T>C​(p.Leu137Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GUCA1C NM_005459.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

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]

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=0.21947685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1C	NM_005459.4	c.410T>C	p.Leu137Ser	missense_variant	3/4	ENST00000261047.8	NP_005450.3
GUCA1C	NM_001363884.1	c.410T>C	p.Leu137Ser	missense_variant	3/4		NP_001350813.1
GUCA1C	XM_011513334.3	c.158T>C	p.Leu53Ser	missense_variant	3/4		XP_011511636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1C	ENST00000261047.8	c.410T>C	p.Leu137Ser	missense_variant	3/4	1	NM_005459.4	ENSP00000261047	P1
GUCA1C	ENST00000393963.7	c.410T>C	p.Leu137Ser	missense_variant	3/4	1		ENSP00000377535
GUCA1C	ENST00000471108.1	c.410T>C	p.Leu137Ser	missense_variant	3/3	2		ENSP00000417761

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2024

The c.410T>C (p.L137S) alteration is located in exon 3 (coding exon 3) of the GUCA1C gene. This alteration results from a T to C substitution at nucleotide position 410, causing the leucine (L) at amino acid position 137 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.036	.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	.;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.41	T;T;T
Polyphen		0.43	B;P;.
Vest4		0.25
MutPred		0.40		Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);
MVP		0.80
MPC		0.13
ClinPred		0.47	T
GERP RS		2.9
Varity_R		0.21
gMVP		0.55

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: rs1946508819; hg19: chr3-108635006;