9-6533010-C-G

Variant names:

• chr9-6533010-C-G
• rs2228098
• ENST00000638233.1:n.1505G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000638233.1(GLDC):​n.1505G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,595,334 control chromosomes in the GnomAD database, including 337,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34684 hom., cov: 31)
  • Exomes 𝑓: 0.64 (303269 hom.)
• Consequence: GLDC ENST00000638233.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.367
• Publications: 13 publications found

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

GLDC Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
• glycine encephalopathy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-6533010-C-G is Benign according to our data. Variant chr9-6533010-C-G is described in ClinVar as Benign. ClinVar VariationId is 255452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.*7G>C		3_prime_UTR_variant	Exon 25 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.*7G>C		3_prime_UTR_variant	Exon 25 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101921 AN: 151884 Hom.: 34653 Cov.: 31

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.647

GnomAD2 exomes AF: 0.691 AC: 173606 AN: 251322 AF XY: 0.681

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.950

Gnomad FIN exome AF: 0.661

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.644 AC: 929353 AN: 1443332 Hom.: 303269 Cov.: 28 AF XY: 0.644 AC XY: 463251 AN XY: 719074

African (AFR) AF: 0.722 AC: 23885 AN: 33076

American (AMR) AF: 0.786 AC: 35150 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16870 AN: 26022

East Asian (EAS) AF: 0.955 AC: 37818 AN: 39616

South Asian (SAS) AF: 0.715 AC: 61354 AN: 85832

European-Finnish (FIN) AF: 0.664 AC: 35462 AN: 53390

Middle Eastern (MID) AF: 0.631 AC: 3178 AN: 5038

European-Non Finnish (NFE) AF: 0.617 AC: 676615 AN: 1095896

Other (OTH) AF: 0.653 AC: 39021 AN: 59756

GnomAD4 genome AF: 0.671 AC: 102005 AN: 152002 Hom.: 34684 Cov.: 31 AF XY: 0.675 AC XY: 50168 AN XY: 74278

African (AFR) AF: 0.717 AC: 29697 AN: 41442

American (AMR) AF: 0.709 AC: 10834 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2208 AN: 3470

East Asian (EAS) AF: 0.947 AC: 4913 AN: 5186

South Asian (SAS) AF: 0.715 AC: 3440 AN: 4808

European-Finnish (FIN) AF: 0.649 AC: 6851 AN: 10554

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42057 AN: 67954

Other (OTH) AF: 0.646 AC: 1365 AN: 2112

Alfa AF: 0.632 Hom.: 9799

Bravo AF: 0.676

Asia WGS AF: 0.822 AC: 2858 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Benign:4

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.60
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228098; hg19: chr9-6533010; COSMIC: COSV58684284;