2-85544938-A-AT

Variant names:

• chr2-85544938-A-AT
• rs886056355
• NM_000821.7:c.*4995dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000821.7(GGCX):​c.*4995dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 147,262 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GGCX NM_000821.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.263
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00359 (528/147262) while in subpopulation AFR AF = 0.0115 (464/40382). AF 95% confidence interval is 0.0106. There are 2 homozygotes in GnomAd4. There are 251 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGCX	NM_000821.7	c.*4995dupA		3_prime_UTR_variant	Exon 15 of 15	ENST00000233838.9	NP_000812.2
MAT2A	NM_005911.6	c.*1178dupT		3_prime_UTR_variant	Exon 9 of 9	ENST00000306434.8	NP_005902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGCX	ENST00000233838.9	c.*4995dupA		3_prime_UTR_variant	Exon 15 of 15	1	NM_000821.7	ENSP00000233838.3
MAT2A	ENST00000306434.8	c.*1178dupT		3_prime_UTR_variant	Exon 9 of 9	1	NM_005911.6	ENSP00000303147.3

Frequencies

GnomAD3 genomes AF: 0.00360 AC: 530 AN: 147196 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000951

Gnomad ASJ AF: 0.000589

Gnomad EAS AF: 0.000796

Gnomad SAS AF: 0.000645

Gnomad FIN AF: 0.000315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000497

Gnomad OTH AF: 0.00250

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00278 AC: 1 AN: 360 Hom.: 0 Cov.: 0 AF XY: 0.00424 AC XY: 1 AN XY: 236

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 350

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AF: 0.00 AC: 0 AN: 4

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00359 AC: 528 AN: 147262 Hom.: 2 Cov.: 32 AF XY: 0.00350 AC XY: 251 AN XY: 71666

African (AFR) AF: 0.0115 AC: 464 AN: 40382

American (AMR) AF: 0.000950 AC: 14 AN: 14730

Ashkenazi Jewish (ASJ) AF: 0.000589 AC: 2 AN: 3396

East Asian (EAS) AF: 0.000798 AC: 4 AN: 5010

South Asian (SAS) AF: 0.000647 AC: 3 AN: 4636

European-Finnish (FIN) AF: 0.000315 AC: 3 AN: 9510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 278

European-Non Finnish (NFE) AF: 0.000497 AC: 33 AN: 66402

Other (OTH) AF: 0.00248 AC: 5 AN: 2016

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin K-Dependent Clotting Factors Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism

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: rs886056355; hg19: chr2-85772061;