rs141601131

Variant names:

• chr9-6645310-C-A
• rs141601131
• NM_000170.3:c.190G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-6645310-C-A
• chr9-6645310-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000170.3(GLDC):​c.190G>T​(p.Ala64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,594,386 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A64T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.758
• Publications: 5 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

LINC02851 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000170.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.017509818).
• BP6: Variant 9-6645310-C-A is Benign according to our data. Variant chr9-6645310-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 462861.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.190G>T	p.Ala64Ser	missense	Exon 1 of 25	NP_000161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.190G>T	p.Ala64Ser	missense	Exon 1 of 25	ENSP00000370737.4
	LINC02851	ENST00000813373.1		n.124+384C>A		intron	N/A
	LINC02851	ENST00000813380.1		n.405+384C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000412 AC: 88 AN: 213782 AF XY: 0.000412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000760

GnomAD4 exome AF: 0.000257 AC: 370 AN: 1442144 Hom.: 1 Cov.: 32 AF XY: 0.000275 AC XY: 197 AN XY: 716382

African (AFR) AF: 0.000156 AC: 5 AN: 32036

American (AMR) AF: 0.000678 AC: 29 AN: 42772

Ashkenazi Jewish (ASJ) AF: 0.00388 AC: 99 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 38280

South Asian (SAS) AF: 0.000300 AC: 25 AN: 83324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51866

Middle Eastern (MID) AF: 0.00275 AC: 13 AN: 4720

European-Non Finnish (NFE) AF: 0.000141 AC: 156 AN: 1104132

Other (OTH) AF: 0.000723 AC: 43 AN: 59478

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74446

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.000849 AC: 13 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67974

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.000400

ExAC AF: 0.000224 AC: 27

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Glycine encephalopathy (2)
-	-	1	GLDC-related disorder (1)
-	1	-	Glycine encephalopathy 1 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.76
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.32
Sift	Benign	0.55	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.24		Gain of phosphorylation at A64 (P = 0.0201)
MVP		0.92
MPC		0.044
ClinPred		0.020	T
GERP RS		2.8
PromoterAI		-0.0089	Neutral
Varity_R		0.20
gMVP		0.50
Mutation Taster		=78/22	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: rs141601131; hg19: chr9-6645310;