Genetic Variant NM_022130.4:c.634C>A (chr5-32126475-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022130.4(GOLPH3):c.634C>A(p.Arg212Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,094 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R212C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GOLPH3
NM_022130.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.60

Publications

0 publications found

Variant links:

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]

GOLPH3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
GOLPH3	NM_022130.4 link	c.634C>A	p.Arg212Ser	missense_variant	Exon 4 of 4	ENST00000265070.7	NP_071413.1	Q9H4A6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GOLPH3	ENST00000265070.7 link	c.634C>A	p.Arg212Ser	missense_variant	Exon 4 of 4	1	NM_022130.4	ENSP00000265070.6	Q9H4A6
GOLPH3	ENST00000503610.5 link	n.*416C>A		non_coding_transcript_exon_variant	Exon 4 of 4	3		ENSP00000426752.1	D6REM1
GOLPH3	ENST00000503610.5 link	n.*416C>A		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000426752.1	D6REM1
GOLPH3	ENST00000512668.1 link	n.*120C>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41382

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.73

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.4

PhyloP100

9.6

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.41

Sift

Benign

0.15

Sift4G

Benign

0.36

Polyphen

0.88

Vest4

0.69

MutPred

0.65

Loss of MoRF binding (P = 0.0107);

MVP

0.59

MPC

1.1

ClinPred

0.96

GERP RS

5.3

Varity_R

0.78

gMVP

0.74

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over