chr4-155759844-G-A

Variant names:

• chr4-155759844-G-A
• rs1477147477
• ENST00000507146:c.-144G>A

Variant summary

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

The NM_001291952.3(GUCY1B1):​c.-152G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000685 in 1,460,402 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCY1B1 NM_001291952.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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.61G>A	p.Val21Met	missense_variant	Exon 2 of 14	ENST00000264424.13	NP_000848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1B1	ENST00000264424.13	c.61G>A	p.Val21Met	missense_variant	Exon 2 of 14	1	NM_000857.5	ENSP00000264424.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460402 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726520

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61G>A (p.V21M) alteration is located in exon 2 (coding exon 2) of the GUCY1B3 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the valine (V) at amino acid position 21 to be replaced by a methionine (M). 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	0.21
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;.
Eigen	Benign	0.080
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.4	.;L;L
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.053	T;T;T
Sift4G	Benign	0.074	T;T;T
Polyphen		0.54	P;P;D
Vest4		0.30
MutPred		0.75		Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);Gain of disorder (P = 0.07);
MVP		0.61
MPC		1.6
ClinPred		0.90	D
GERP RS		3.2
Varity_R		0.23
gMVP		0.92

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: rs1477147477; hg19: chr4-156680996;