2-85545505-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000821.7(GGCX):c.*4429G>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 0.113 in 152,198 control chromosomes in the GnomAD database, including 1,009 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1009 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

GGCX
NM_000821.7 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.317

Publications

4 publications found

Variant links:

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]

GGCX links:

MAT2A (HGNC:6904): (methionine adenosyltransferase 2A) The protein encoded by this gene catalyzes the production of S-adenosylmethionine (AdoMet) from methionine and ATP. AdoMet is the key methyl donor in cellular processes. [provided by RefSeq, Jun 2011]

MAT2A Gene-Disease associations (from GenCC):

familial thoracic aortic aneurysm and aortic dissection
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MAT2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 2-85545505-C-T is Benign according to our data. Variant chr2-85545505-C-T is described in ClinVar as [Benign]. Clinvar id is 337180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7 link	c.*4429G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000233838.9	NP_000812.2	P38435-1
MAT2A	NM_005911.6 link	c.*1733C>T		downstream_gene_variant		ENST00000306434.8	NP_005902.1	P31153-1A0A140VJP5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9 link	c.*4429G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_000821.7	ENSP00000233838.3		P38435-1
MAT2A	ENST00000306434.8 link	c.*1733C>T		downstream_gene_variant		1	NM_005911.6	ENSP00000303147.3		P31153-1

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17119

AN:

152080

Hom.:

1008

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.0598

Gnomad SAS

AF:

0.186

Gnomad FIN

AF:

0.0788

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.124

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.113

AC:

17130

AN:

152198

Hom.:

1009

Cov.:

AF XY:

0.113

AC XY:

8419

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.107

AC:

4457

AN:

41494

American (AMR)

AF:

0.115

AC:

1758

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

429

AN:

3472

East Asian (EAS)

AF:

0.0595

AC:

309

AN:

5192

South Asian (SAS)

AF:

0.186

AC:

895

AN:

4820

European-Finnish (FIN)

AF:

0.0788

AC:

834

AN:

10590

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8080

AN:

68018

Other (OTH)

AF:

0.122

AC:

258

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

804

1608

2411

3215

4019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.120

Hom.:

511

Bravo

AF:

0.113

Asia WGS

AF:

0.122

AC:

425

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.2

(source)

DANN

Benign

0.40

PhyloP100

0.32

Mutation Taster

=100/0

polymorphism (auto)

(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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2-85545505-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over