rs144241950

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_000481.4(AMT):c.825T>A(p.Asn275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000475 in 1,613,788 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00049 ( 1 hom. )

Consequence

AMT
NM_000481.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.18

Publications

3 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: Likely_benign. The variant received -1 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000481.4

BP4

Computational evidence support a benign effect (MetaRNN=0.15064928).

BP6

Variant 3-49419023-A-T is Benign according to our data. Variant chr3-49419023-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 346031.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4 link	c.825T>A	p.Asn275Lys	missense_variant	Exon 7 of 9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9 link	c.825T>A	p.Asn275Lys	missense_variant	Exon 7 of 9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1 link	c.1062T>A	p.Asn354Lys	missense_variant	Exon 9 of 11	5		ENSP00000490106.1

Frequencies

GnomAD3 genomes

AF:

0.000290

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.000327

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:

0.000456

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000330

AC:

AN:

251364

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000495

AC:

723

AN:

1461810

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

363

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000937

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000612

AC:

680

AN:

1112008

Other (OTH)

AF:

0.000281

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.000290

AC:

AN:

151978

Hom.:

Cov.:

AF XY:

0.000216

AC XY:

AN XY:

74214

show subpopulations

African (AFR)

AF:

0.0000967

AC:

AN:

41368

American (AMR)

AF:

0.000327

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2086

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:

0.000549

Hom.:

Bravo

AF:

0.000355

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycine encephalopathy

Uncertain:3Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not specified

Uncertain:1

Jul 02, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: AMT c.825T>A (p.Asn275Lys) results in a non-conservative amino acid change located in the Aminomethyltransferase, folate-binding domain (IPR006222) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AMT causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) (0.00033 vs 0.0014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.825T>A in individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) and no experimental evidence demonstrating its impact on protein function have been reported. The following publication reporting a non-ascertainable evidence has been cited in the context of this evaluation (PMID: 22171071). ClinVar contains an entry for this variant (Variation ID: 346031). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.34

CADD

Benign

3.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

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

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.67

LIST_S2

Benign

0.84

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

3.4

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

PhyloP100

-1.2

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.9

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

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0080

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

Vest4

0.43

ClinPred

0.23

GERP RS

-2.2

PromoterAI

0.011

Neutral

(source)

Varity_R

0.83

gMVP

0.90

Mutation Taster

=31/69

disease causing

(source)

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

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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