1-235342645-AC-GT

Variant names:

• chr1-235342645-AC-GT
• NM_004837.4:c.776_777delACinsGT
• GGPS1 p.Tyr259Cys

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM1 PP2 PP3

The NM_004837.4(GGPS1):​c.776_777delACinsGT​(p.Tyr259Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GGPS1 NM_004837.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• Publications: 0 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.

• PS1: Transcript NM_004837.4 (GGPS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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
• 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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.776_777delACinsGT	p.Tyr259Cys	missense	N/A	NP_004828.1	O95749-1
	GGPS1	NM_001037277.1		c.776_777delACinsGT	p.Tyr259Cys	missense	N/A	NP_001032354.1	O95749-1
	GGPS1	NM_001371477.1		c.776_777delACinsGT	p.Tyr259Cys	missense	N/A	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.776_777delACinsGT	p.Tyr259Cys	missense	N/A	ENSP00000282841.5	O95749-1
	GGPS1	ENST00000488594.5	TSL:1	c.776_777delACinsGT	p.Tyr259Cys	missense	N/A	ENSP00000418690.1	O95749-1
	ENSG00000285053	ENST00000647186.1		c.-435+7311_-435+7312delACinsGT		intron	N/A	ENSP00000494775.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-235505960;