Genetic Variant GGPS1:p.Arg261Gly (chr1-235342650-C-G) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3PP5

The NM_004837.4(GGPS1):c.781C>G(p.Arg261Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,610,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R261H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

GGPS1
NM_004837.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.91

Publications

2 publications found

Variant links:

Genes affected

GGPS1 (HGNC:4249): (geranylgeranyl diphosphate synthase 1) This gene is a member of the prenyltransferase family and encodes a protein with geranylgeranyl diphosphate (GGPP) synthase activity. The enzyme catalyzes the synthesis of GGPP from farnesyl diphosphate and isopentenyl diphosphate. GGPP is an important molecule responsible for the C20-prenylation of proteins and for the regulation of a nuclear hormone receptor. Alternate transcriptional splice variants, both protein-coding and non-protein-coding, have been found for this gene. [provided by RefSeq, Sep 2010]

GGPS1 Gene-Disease associations (from GenCC):

muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

GGPS1 links:

ENSG00000285053 (HGNC:):

ENSG00000285053 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004837.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-235342651-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 869200.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.2153 (below the threshold of 3.09). Trascript score misZ: 1.3999 (below the threshold of 3.09). GenCC associations: The gene is linked to muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.754

PP5

Variant 1-235342650-C-G is Pathogenic according to our data. Variant chr1-235342650-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1232301.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004837.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGPS1	NM_004837.4	MANE Select	c.781C>G	p.Arg261Gly	missense	Exon 4 of 4	NP_004828.1	O95749-1
GGPS1	NM_001037277.1		c.781C>G	p.Arg261Gly	missense	Exon 4 of 4	NP_001032354.1	O95749-1
GGPS1	NM_001371477.1		c.781C>G	p.Arg261Gly	missense	Exon 4 of 4	NP_001358406.1	O95749-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GGPS1	ENST00000282841.9	TSL:1 MANE Select	c.781C>G	p.Arg261Gly	missense	Exon 4 of 4	ENSP00000282841.5	O95749-1
GGPS1	ENST00000488594.5	TSL:1	c.781C>G	p.Arg261Gly	missense	Exon 4 of 4	ENSP00000418690.1	O95749-1
ENSG00000285053	ENST00000647186.1		c.-435+7316C>G		intron	N/A	ENSP00000494775.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152122

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251212

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458420

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

725730

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39676

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1108830

Other (OTH)

AF:

0.0000995

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

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:

41420

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.045

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.0

PhyloP100

1.9

PrimateAI

Benign

0.35

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.40

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.026

Polyphen

0.71

Vest4

0.64

MutPred

0.59

Loss of stability (P = 0.0279)

MVP

0.52

MPC

0.77

ClinPred

0.97

GERP RS

3.3

Varity_R

0.72

gMVP

0.78

Mutation Taster

=28/72

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over