chr1-235335308-C-T

Variant names:

• chr1-235335308-C-T
• rs1157311940
• NM_004837.4:c.44C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_004837.4(GGPS1):​c.44C>T​(p.Pro15Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000216 in 1,391,560 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: GGPS1 NM_004837.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.25
• 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 7 ACMG points.

• 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, 0.951

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.44C>T	p.Pro15Leu	missense	Exon 2 of 4	NP_004828.1	O95749-1
	GGPS1	NM_001037277.1		c.44C>T	p.Pro15Leu	missense	Exon 2 of 4	NP_001032354.1	O95749-1
	GGPS1	NM_001371477.1		c.44C>T	p.Pro15Leu	missense	Exon 2 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.44C>T	p.Pro15Leu	missense	Exon 2 of 4	ENSP00000282841.5	O95749-1
	GGPS1	ENST00000488594.5	TSL:1	c.44C>T	p.Pro15Leu	missense	Exon 2 of 4	ENSP00000418690.1	O95749-1
	ENSG00000285053	ENST00000647186.1		c.-461C>T		5_prime_UTR	Exon 2 of 19	ENSP00000494775.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000216 AC: 3 AN: 1391560 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 696346

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

African (AFR) AF: 0.00 AC: 0 AN: 32142

American (AMR) AF: 0.00 AC: 0 AN: 43918

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25644

East Asian (EAS) AF: 0.00 AC: 0 AN: 39294

South Asian (SAS) AF: 0.00 AC: 0 AN: 84140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000286 AC: 3 AN: 1049960

Other (OTH) AF: 0.00 AC: 0 AN: 57992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0136242), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.8	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.83		Gain of MoRF binding (P = 0.0654)
MVP		0.62
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.87
Mutation Taster		=16/84	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: rs1157311940; hg19: chr1-235498623;