chr3-49417550-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 2.02
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
AMTNM_000481.4 linkuse as main transcriptc.1202C>A p.Thr401Asn missense_variant 9/9 ENST00000273588.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AMTENST00000273588.9 linkuse as main transcriptc.1202C>A p.Thr401Asn missense_variant 9/91 NM_000481.4 P1P48728-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Jun 22, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 09, 2022This 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. -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs752952950; hg19: chr3-49454983; API