chr3-49422261-C-T

Position:

chr3-49422261-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000273588.9(AMT):c.101G>A(p.Arg34His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,614,046 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R34C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00063 ( 3 hom. )

Consequence

AMT
ENST00000273588.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.312

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009922236).

BP6

Variant 3-49422261-C-T is Benign according to our data. Variant chr3-49422261-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531783.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMT	NM_000481.4 linkuse as main transcript	c.101G>A	p.Arg34His	missense_variant	2/9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9 linkuse as main transcript	c.101G>A	p.Arg34His	missense_variant	2/9	1	NM_000481.4	ENSP00000273588	P1	P48728-1

Frequencies

GnomAD3 genomes

AF:

0.000545

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.000804

AC:

202

AN:

251204

Hom.:

AF XY:

0.000803

AC XY:

109

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00834

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000564

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000629

AC:

920

AN:

1461706

Hom.:

Cov.:

AF XY:

0.000619

AC XY:

450

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00677

Gnomad4 EAS exome

AF:

0.000630

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000517

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000551

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000913

Hom.:

Bravo

AF:

0.000767

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000692

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Non-ketotic hyperglycinemia

Uncertain:1Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 10, 2023

Variant summary: AMT c.101G>A (p.Arg34His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 1461706 control chromosomes, predominantly at a frequency of 0.0026 within the Middle Eastern subpopulation in the gnomAD database, and it is present in three homozygotes across all subpopulations. The observed variant frequency is 1.86-fold of the estimated maximal expected allele frequency for a pathogenic variant in AMT causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.0026 vs. 0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Middle Eastern origin. To our knowledge, no occurrence of c.101G>A in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One classified the variant as uncertain significance, and two classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

AMT-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;T;.;.;T;T;.;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.0099

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

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.9

L;.;L;L;.;.;.;.

MutationTaster

Benign

0.92

D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.24

Sift

Benign

0.034

D;.;D;D;.;.;.;.

Sift4G

Benign

0.086

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

Polyphen

0.043

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

Vest4

0.31

MVP

0.89

MPC

0.26

ClinPred

0.031

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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