chr3-49417550-G-T

Position:

• chr3-49417550-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000481.4(AMT):​c.1202C>A​(p.Thr401Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T401T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (1 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.02

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12521046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMT	NM_000481.4	c.1202C>A	p.Thr401Asn	missense_variant	9/9	ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMT	ENST00000273588.9	c.1202C>A	p.Thr401Asn	missense_variant	9/9	1	NM_000481.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251468 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461894 Hom.: 1 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 401 of the AMT protein (p.Thr401Asn). This variant is present in population databases (rs752952950, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 1052844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt AMT protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	7.5
DANN	Benign	0.70
DEOGEN2	Benign	0.39	T;T;.;T;T;T;.;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.81
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.96	L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.90	D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;.;N;.;.;.;.;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.49	T;.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;.;T;.;.;.;.;.;.;.
Polyphen		0.0	B;.;.;.;.;.;.;.;.;.
Vest4		0.14
MutPred		0.36		Loss of phosphorylation at T401 (P = 0.0493);.;.;.;.;.;.;.;.;.;
MVP		0.89
MPC		0.24
ClinPred		0.025	T
GERP RS		1.4
Varity_R		0.13
gMVP		0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs752952950; hg19: chr3-49454983;