chr3-49419023-A-T

Position:

• chr3-49419023-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000273588.9(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 ENST00000273588.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -1.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000273588.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15064928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMT	NM_000481.4	c.825T>A	p.Asn275Lys	missense_variant	7/9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.825T>A	p.Asn275Lys	missense_variant	7/9	1	NM_000481.4	ENSP00000273588	P1

Frequencies

GnomAD3 genomes AF: 0.000290 AC: 44 AN: 151978 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.000330 AC: 83 AN: 251364 Hom.: 0 AF XY: 0.000309 AC XY: 42 AN XY: 135894

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 SAS exome AF: 0.000163

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.: 1 Cov.: 31 AF XY: 0.000499 AC XY: 363 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.000612

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000290 AC: 44 AN: 151978 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 74214

Gnomad4 AFR AF: 0.0000967

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000549 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000600

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 10, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 16, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 02, 2024

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	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	3.1
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;T;.;.;D;T;T;.;.;D;T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.4	M;.;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.9	D;.;D;D;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D;.;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0080	D;.;D;D;.;.;.;.;.;.;.;.;.
Polyphen		0.97	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.43
MutPred		0.67		Loss of stability (P = 0.0043);.;Loss of stability (P = 0.0043);.;.;Loss of stability (P = 0.0043);.;.;.;.;.;.;.;
MVP		0.74
MPC		0.33
ClinPred		0.23	T
GERP RS		-2.2
Varity_R		0.83
gMVP		0.90

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

Other links and lift over

dbSNP: rs144241950; hg19: chr3-49456456;