NM_000481.4:c.515T>C

Variant names:

• chr3-49419745-A-G
• rs1366977126
• NM_000481.4:c.515T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_000481.4(AMT):​c.515T>C​(p.Leu172Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L172L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 7.65
• Publications: 1 publications found

Genes affected

AMT (HGNC:473): (aminomethyltransferase) This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

AMT Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• glycine encephalopathy 2

  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

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 3-49419745-A-G is Pathogenic according to our data. Variant chr3-49419745-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558446.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000481.4. 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
	AMT	NM_000481.4	MANE Select	c.515T>C	p.Leu172Pro	missense	Exon 5 of 9	NP_000472.2
	AMT	NM_001164712.2		c.515T>C	p.Leu172Pro	missense	Exon 5 of 10	NP_001158184.1	P48728-4
	AMT	NM_001164710.2		c.383T>C	p.Leu128Pro	missense	Exon 4 of 8	NP_001158182.1	P48728-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.515T>C	p.Leu172Pro	missense	Exon 5 of 9	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.752T>C	p.Leu251Pro	missense	Exon 7 of 11	ENSP00000490106.1	A0A1B0GUH1
	AMT	ENST00000395338.7	TSL:1	c.515T>C	p.Leu172Pro	missense	Exon 5 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Glycine encephalopathy 1 (2)
1	-	-	Glycine encephalopathy (1)
1	-	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.62		Gain of disorder (P = 0.0205)
MVP		0.95
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.97
Mutation Taster		=0/100	disease causing

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: rs1366977126; hg19: chr3-49457178;