chr9-6533010-C-G

Variant names:

• chr9-6533010-C-G
• rs2228098
• NM_000170.3:c.*7G>C

Variant summary

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

The NM_000170.3(GLDC):​c.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 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 NM_000170.3 3_prime_UTR
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.*7G>C		3_prime_UTR	Exon 25 of 25	NP_000161.2	P23378

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.*7G>C		3_prime_UTR	Exon 25 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000638233.1	TSL:1	n.1505G>C		non_coding_transcript_exon	Exon 11 of 11
	GLDC	ENST00000639443.1	TSL:1	n.2638G>C		non_coding_transcript_exon	Exon 21 of 21

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycine encephalopathy (4)
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;