chr5-32126346-G-A

Variant names:

• chr5-32126346-G-A
• rs1476174592
• NM_022130.4:c.763C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022130.4(GOLPH3):​c.763C>T​(p.Pro255Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: GOLPH3 NM_022130.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.78
• Publications: 0 publications found

Genes affected

GOLPH3 (HGNC:15452): (golgi phosphoprotein 3) The Golgi complex plays a key role in the sorting and modification of proteins exported from the endoplasmic reticulum. The protein encoded by this gene is a peripheral membrane protein of the Golgi stack and may have a regulatory role in Golgi trafficking. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of these variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34144044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOLPH3	NM_022130.4	c.763C>T	p.Pro255Ser	missense_variant	Exon 4 of 4	ENST00000265070.7	NP_071413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOLPH3	ENST00000265070.7	c.763C>T	p.Pro255Ser	missense_variant	Exon 4 of 4	1	NM_022130.4	ENSP00000265070.6
GOLPH3	ENST00000503610.5	n.*545C>T		downstream_gene_variant		3		ENSP00000426752.1
GOLPH3	ENST00000512668.1	n.*249C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763C>T (p.P255S) alteration is located in exon 4 (coding exon 4) of the GOLPH3 gene. This alteration results from a C to T substitution at nucleotide position 763, causing the proline (P) at amino acid position 255 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	0.21
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.096
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.29
Sift	Benign	0.84	T
Sift4G	Benign	0.61	T
Polyphen		0.34	B
Vest4		0.43
MutPred		0.46		Loss of stability (P = 0.1331);
MVP		0.76
MPC		0.75
ClinPred		0.81	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.69
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1476174592; hg19: chr5-32126452; COSMIC: COSV54060482; COSMIC: COSV54060482;