rs121964985

Variant names:

• chr3-49417892-C-A
• rs121964985
• NM_000481.4:c.959G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-49417892-C-A
• chr3-49417892-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000481.4(AMT):​c.959G>T​(p.Arg320Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,794 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.09
• Publications: 11 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-49417893-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3340315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

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.959G>T	p.Arg320Leu	missense	Exon 8 of 9	NP_000472.2
	AMT	NM_001164712.2		c.959G>T	p.Arg320Leu	missense	Exon 8 of 10	NP_001158184.1	P48728-4
	AMT	NM_001164710.2		c.827G>T	p.Arg276Leu	missense	Exon 7 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.959G>T	p.Arg320Leu	missense	Exon 8 of 9	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.1196G>T	p.Arg399Leu	missense	Exon 10 of 11	ENSP00000490106.1	A0A1B0GUH1
	AMT	ENST00000395338.7	TSL:1	c.959G>T	p.Arg320Leu	missense	Exon 8 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251190 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.5	L
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.64		Loss of methylation at R320 (P = 0.0234)
MVP		0.86
MPC		0.80
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.89
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121964985; hg19: chr3-49455325;