2-85545425-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.*4509G>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 0.514 in 152,128 control chromosomes in the GnomAD database, including 21,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 21084 hom., cov: 32)

Exomes 𝑓: 0.46 ( 15 hom. )

Consequence

GGCX
NM_000821.7 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.876

Publications

23 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=-0.81).

BP6

Variant 2-85545425-C-T is Benign according to our data. Variant chr2-85545425-C-T is described in ClinVar as [Benign]. Clinvar id is 337179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7 link	c.*4509G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000233838.9	NP_000812.2	P38435-1
MAT2A	NM_005911.6 link	c.*1653C>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.*4509G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_000821.7	ENSP00000233838.3		P38435-1
MAT2A	ENST00000306434.8 link	c.*1653C>T		downstream_gene_variant		1	NM_005911.6	ENSP00000303147.3		P31153-1

Frequencies

GnomAD3 genomes

AF:

0.514

AC:

78047

AN:

151850

Hom.:

21044

Cov.:

show subpopulations

Gnomad AFR

AF:

0.685

Gnomad AMI

AF:

0.459

Gnomad AMR

AF:

0.423

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.390

Gnomad SAS

AF:

0.391

Gnomad FIN

AF:

0.457

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.465

Gnomad OTH

AF:

0.506

GnomAD4 exome

AF:

0.456

AC:

AN:

160

Hom.:

Cov.:

AF XY:

0.480

AC XY:

AN XY:

102

show subpopulations

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)

AF:

0.462

AC:

AN:

158

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.514

AC:

78143

AN:

151968

Hom.:

21084

Cov.:

AF XY:

0.510

AC XY:

37908

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.685

AC:

28394

AN:

41438

American (AMR)

AF:

0.422

AC:

6441

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1390

AN:

3466

East Asian (EAS)

AF:

0.390

AC:

2016

AN:

5168

South Asian (SAS)

AF:

0.391

AC:

1888

AN:

4824

European-Finnish (FIN)

AF:

0.457

AC:

4813

AN:

10524

Middle Eastern (MID)

AF:

0.449

AC:

132

AN:

294

European-Non Finnish (NFE)

AF:

0.465

AC:

31576

AN:

67956

Other (OTH)

AF:

0.508

AC:

1074

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1841

3682

5522

7363

9204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.500

Hom.:

2558

Bravo

AF:

0.518

Asia WGS

AF:

0.439

AC:

1530

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 12, 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

-0.81

CADD

Benign

0.42

(source)

DANN

Benign

0.46

PhyloP100

-0.88

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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2-85545425-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