3-49422374-A-T

Position:

chr3-49422374-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000481.4(AMT):c.77T>A(p.Leu26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

AMT
NM_000481.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.44

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]

AMT links:

NICN1 (HGNC:18317): (nicolin 1, tubulin polyglutamylase complex subunit) This protein encoded by this gene localizes to the nucleus and is expressed in numerous tissues including brain, testis, liver, and kidney. This refseq contains genomic sequence in its 3' UTR which is not supported by experimental evidence. Computer predictions indicate that this region of the 3' UTR contains hairpin-forming self-complementary sequence which is possibly excised after transcription. This gene has a pseudogene on chromosome X. [provided by RefSeq, Jul 2008]

NICN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28151435).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMT	NM_000481.4 linkuse as main transcript	c.77T>A	p.Leu26His	missense_variant	1/9	ENST00000273588.9	NP_000472.2
NICN1	NM_032316.3 linkuse as main transcript	c.*2459T>A		3_prime_UTR_variant	6/6	ENST00000273598.8	NP_115692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9 linkuse as main transcript	c.77T>A	p.Leu26His	missense_variant	1/9	1	NM_000481.4	ENSP00000273588	P1	P48728-1
NICN1	ENST00000273598.8 linkuse as main transcript	c.*2459T>A		3_prime_UTR_variant	6/6	1	NM_032316.3	ENSP00000273598	P1	Q9BSH3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251140

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135808

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.77T>A (p.L26H) alteration is located in exon 1 (coding exon 1) of the AMT gene. This alteration results from a T to A substitution at nucleotide position 77, causing the leucine (L) at amino acid position 26 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Non-ketotic hyperglycinemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 03, 2022

This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 26 of the AMT protein (p.Leu26His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with AMT-related conditions. 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

0.11

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.38

T;T;.;.;T;T;.;T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.82

T;T;T;T;T;T;T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.28

T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.049

MutationAssessor

Uncertain

2.0

M;.;M;M;.;.;.;.;M

MutationTaster

Benign

0.64

D;D;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.90

N;.;N;N;.;.;.;.;.

REVEL

Uncertain

0.35

Sift

Benign

0.24

T;.;T;T;.;.;.;.;.

Sift4G

Benign

0.50

T;.;T;T;.;.;.;.;.

Polyphen

0.31

B;.;.;.;.;.;.;.;.

Vest4

0.19

MutPred

0.52

Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);Gain of catalytic residue at L26 (P = 0.0028);

MVP

0.75

MPC

0.27

ClinPred

0.34

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.43

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over