2-85544938-A-AT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000821.7(GGCX):c.*4995_*4996insA 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 2 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGCX	NM_000821.7	c.*4995_*4996insA		3_prime_UTR_variant	15/15	ENST00000233838.9
MAT2A	NM_005911.6	c.*1178dup		3_prime_UTR_variant	9/9	ENST00000306434.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGCX	ENST00000233838.9	c.*4995_*4996insA		3_prime_UTR_variant	15/15	1	NM_000821.7	P1
MAT2A	ENST00000306434.8	c.*1178dup		3_prime_UTR_variant	9/9	1	NM_005911.6	P1

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

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0115

Gnomad4 AMR AF: 0.000950

Gnomad4 ASJ AF: 0.000589

Gnomad4 EAS AF: 0.000798

Gnomad4 SAS AF: 0.000647

Gnomad4 FIN AF: 0.000315

Gnomad4 NFE AF: 0.000497

Gnomad4 OTH AF: 0.00248

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin K-Dependent Clotting Factors Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs886056355; hg19: chr2-85772061;