NM_000481.4:c.898A>G

Variant names:

• chr3-49417953-T-C
• rs144971200
• NM_000481.4:c.898A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000481.4(AMT):​c.898A>G​(p.Met300Val) variant causes a missense change. The variant allele was found at a frequency of 0.000684 in 1,613,254 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.07
• Publications: 3 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000481.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009899169).
• BP6: Variant 3-49417953-T-C is Benign according to our data. Variant chr3-49417953-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00369 (562/152140) while in subpopulation AFR AF = 0.0128 (531/41510). AF 95% confidence interval is 0.0119. There are 2 homozygotes in GnomAd4. There are 276 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,Unknown gene

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.898A>G	p.Met300Val	missense	Exon 8 of 9	NP_000472.2
	AMT	NM_001164712.2		c.898A>G	p.Met300Val	missense	Exon 8 of 10	NP_001158184.1	P48728-4
	AMT	NM_001164710.2		c.766A>G	p.Met256Val	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.898A>G	p.Met300Val	missense	Exon 8 of 9	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.1135A>G	p.Met379Val	missense	Exon 10 of 11	ENSP00000490106.1	A0A1B0GUH1
	AMT	ENST00000395338.7	TSL:1	c.898A>G	p.Met300Val	missense	Exon 8 of 10	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes AF: 0.00370 AC: 562 AN: 152024 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000993 AC: 247 AN: 248672 AF XY: 0.000720

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000370 AC: 541 AN: 1461114 Hom.: 2 Cov.: 32 AF XY: 0.000319 AC XY: 232 AN XY: 726836

African (AFR) AF: 0.0134 AC: 448 AN: 33462

American (AMR) AF: 0.000762 AC: 34 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53160

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5720

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111760

Other (OTH) AF: 0.000712 AC: 43 AN: 60364

GnomAD4 genome AF: 0.00369 AC: 562 AN: 152140 Hom.: 2 Cov.: 31 AF XY: 0.00371 AC XY: 276 AN XY: 74368

African (AFR) AF: 0.0128 AC: 531 AN: 41510

American (AMR) AF: 0.00137 AC: 21 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00293 Hom.: 2

Bravo AF: 0.00397

ESP6500AA AF: 0.0125 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycine encephalopathy (3)
-	-	3	not provided (3)
-	-	1	Glycine encephalopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.40	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.63	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.90
MPC		0.21
ClinPred		0.026	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.65
Mutation Taster		=90/10	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: rs144971200; hg19: chr3-49455386;