1-235342645-A-G

Variant names:

• chr1-235342645-A-G
• rs2103351693
• NM_004837.4:c.776A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_004837.4(GGPS1):​c.776A>G​(p.Tyr259Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GGPS1 NM_004837.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.29
• Publications: 2 publications found

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)

ENSG00000285053 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 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
• 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, 0.862
• PP5: Variant 1-235342645-A-G is Pathogenic according to our data. Variant chr1-235342645-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1232302.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGPS1	NM_004837.4	MANE Select	c.776A>G	p.Tyr259Cys	missense	Exon 4 of 4	NP_004828.1	O95749-1
	GGPS1	NM_001037277.1		c.776A>G	p.Tyr259Cys	missense	Exon 4 of 4	NP_001032354.1	O95749-1
	GGPS1	NM_001371477.1		c.776A>G	p.Tyr259Cys	missense	Exon 4 of 4	NP_001358406.1	O95749-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGPS1	ENST00000282841.9	TSL:1 MANE Select	c.776A>G	p.Tyr259Cys	missense	Exon 4 of 4	ENSP00000282841.5	O95749-1
	GGPS1	ENST00000488594.5	TSL:1	c.776A>G	p.Tyr259Cys	missense	Exon 4 of 4	ENSP00000418690.1	O95749-1
	ENSG00000285053	ENST00000647186.1		c.-435+7311A>G		intron	N/A	ENSP00000494775.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.66		Loss of phosphorylation at Y259 (P = 0.1177)
MVP		0.53
MPC		1.4
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.88
gMVP		0.78
Mutation Taster		=4/96	disease causing

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: rs2103351693; hg19: chr1-235505960;