rs757918826

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000481.4(AMT):c.794G>A(p.Arg265His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R265C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

AMT
NM_000481.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.47

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

glycine encephalopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
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

AMT links:

ENSG00000283189 (HGNC:):

ENSG00000283189 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-49419055-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 3-49419054-C-T is Pathogenic according to our data. Variant chr3-49419054-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 550886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4 link	c.794G>A	p.Arg265His	missense_variant	Exon 7 of 9	ENST00000273588.9	NP_000472.2	P48728-1A0A024R2U7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9 link	c.794G>A	p.Arg265His	missense_variant	Exon 7 of 9	1	NM_000481.4	ENSP00000273588.3		P48728-1
ENSG00000283189	ENST00000636166.1 link	c.1031G>A	p.Arg344His	missense_variant	Exon 9 of 11	5		ENSP00000490106.1		A0A1B0GUH1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251324

AF XY:

0.0000147

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000927

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111990

Other (OTH)

AF:

0.0000497

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.000196

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Pathogenic:4

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.99; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000550886 / PMID: 25231368). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 25231368, 27362913). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 27362913). A different missense change at the same codon (p.Arg265Cys) has been reported to be associated with AMT related disorder (PMID: 26371980). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 15, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg265 amino acid residue in AMT. Other variant(s) that disrupt this residue have been observed in individuals with AMT-related conditions (PMID: 26371980, 27362913), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt AMT protein function. ClinVar contains an entry for this variant (Variation ID: 550886). This missense change has been observed in individual(s) with glycine¬†encephalopathy (PMID: 27362913). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs757918826, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the AMT protein (p.Arg265His). -

May 16, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AMT c.794G>A (p.Arg265His) results in a non-conservative amino acid change located in the Aminomethyltransferase, folate-binding domain (IPR006222) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251324 control chromosomes. c.794G>A has been reported in the literature in multiple bi-alleleic individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (examples: Azize_2014, Coughlin_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 25231368, 27362913). ClinVar contains an entry for this variant (Variation ID: 550886). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Jun 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27362913, 25231368, 27535533) -

Glycine encephalopathy 2

Pathogenic:1

Nov 19, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycine encephalopathy 1

Pathogenic:1

Mar 15, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.;H;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.9

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

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99

MVP

0.99

MPC

0.89

ClinPred

1.0

GERP RS

5.3

PromoterAI

-0.056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over