2-85545355-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000821.7(GGCX):c.*4579G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 152,678 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (37 hom., cov: 32)
  • Exomes 𝑓: 0.060 (0 hom.)
• Consequence: GGCX NM_000821.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0240

Genes affected

GGCX (HGNC:4247): (gamma-glutamyl carboxylase) This gene encodes an integral membrane protein of the rough endoplasmic reticulum that carboxylates glutamate residues of vitamin K-dependent proteins to gamma carboxyl glutamate, a modification that is required for their activity. The vitamin K-dependent protein substrates have a propeptide that binds the enzyme, with carbon dioxide, dioxide, and reduced vitamin K acting as co-substrates. Vitamin K-dependent proteins affect a number of physiologic processes including blood coagulation, prevention of vascular calcification, and inflammation. Allelic variants of this gene have been associated with pseudoxanthoma elasticum-like disorder with associated multiple coagulation factor deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-85545355-C-T is Benign according to our data. Variant chr2-85545355-C-T is described in ClinVar as [Benign]. Clinvar id is 337176.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest population allele frequency = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.*4579G>A		3_prime_UTR_variant	15/15	ENST00000233838.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.*4579G>A		3_prime_UTR_variant	15/15	1	NM_000821.7	P1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2776 AN: 152124 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00476

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0596 AC: 26 AN: 436 Hom.: 0 Cov.: 0 AF XY: 0.0682 AC XY: 18 AN XY: 264

Gnomad4 FIN exome AF: 0.0590

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.167

GnomAD4 genome AF: 0.0182 AC: 2777 AN: 152242 Hom.: 37 Cov.: 32 AF XY: 0.0185 AC XY: 1374 AN XY: 74454

Gnomad4 AFR AF: 0.00474

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0157

Gnomad4 FIN AF: 0.0411

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0144 Hom.: 4

Bravo AF: 0.0163

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin K-dependent clotting factors, combined deficiency of, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.6
Dann	Benign	0.65

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

LitVar

Other links and lift over

dbSNP: rs138686161; hg19: chr2-85772478;