3-49419382-G-T

Variant names:

• chr3-49419382-G-T
• rs121964986
• NM_000481.4:c.574C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000481.4(AMT):​c.574C>A​(p.Gln192Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q192Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.49
• Publications: 2 publications found

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

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4	c.574C>A	p.Gln192Lys	missense_variant	Exon 6 of 9	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.574C>A	p.Gln192Lys	missense_variant	Exon 6 of 9	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.811C>A	p.Gln271Lys	missense_variant	Exon 8 of 11	5		ENSP00000490106.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;.;D;T;T;.;.;D;T;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.1	D;D;D;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0090	D;D;D;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.10	T;T;T;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.73
MutPred		0.61		Gain of ubiquitination at Q192 (P = 0.0238);Gain of ubiquitination at Q192 (P = 0.0238);.;.;Gain of ubiquitination at Q192 (P = 0.0238);.;.;.;.;.;.;.;
MVP		0.90
MPC		0.88
ClinPred		0.96	D
GERP RS		5.3
PromoterAI		-0.016	Neutral
Varity_R		0.83
gMVP		0.82
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121964986; hg19: chr3-49456815;