NM_000857.5:c.337C>T

Variant names:

• chr4-155789753-C-T
• NM_000857.5:c.337C>T

Variant summary

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

The NM_000857.5(GUCY1B1):​c.337C>T​(p.Pro113Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GUCY1B1 NM_000857.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

Genes affected

GUCY1B1 (HGNC:4687): (guanylate cyclase 1 soluble subunit beta 1) This gene encodes the beta subunit of the soluble guanylate cyclase (sGC), which catalyzes the conversion of GTP (guanosine triphosphate) to cGMP (cyclic guanosine monophosphate). The encoded protein contains an HNOX domain, which serves as a receptor for ligands such as nitric oxide, oxygen and nitrovasodilator drugs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY1B1	NM_000857.5	c.337C>T	p.Pro113Ser	missense_variant	Exon 5 of 14	ENST00000264424.13	NP_000848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1B1	ENST00000264424.13	c.337C>T	p.Pro113Ser	missense_variant	Exon 5 of 14	1	NM_000857.5	ENSP00000264424.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.337C>T (p.P113S) alteration is located in exon 5 (coding exon 5) of the GUCY1B3 gene. This alteration results from a C to T substitution at nucleotide position 337, causing the proline (P) at amino acid position 113 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.061	T;.;.;.;T;.;T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.4	.;.;.;.;M;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.2	D;D;D;D;D;D;D
REVEL	Uncertain	0.35
Sift	Benign	0.12	T;T;T;T;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T;T;T
Polyphen		0.98, 0.89, 0.99, 1.0	.;D;.;P;D;D;.
Vest4		0.75
MutPred		0.72		.;Loss of glycosylation at T132 (P = 0.0264);.;.;.;.;.;
MVP		0.84
MPC		2.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.62
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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.

Other links and lift over

hg19: chr4-156710905;