3-49421493-T-C

Position:

• chr3-49421493-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000481.4(AMT):​c.338A>G​(p.Gln113Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000481.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMT	NM_000481.4	c.338A>G	p.Gln113Arg	missense_variant, splice_region_variant	3/9	ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMT	ENST00000273588.9	c.338A>G	p.Gln113Arg	missense_variant, splice_region_variant	3/9	1	NM_000481.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Benign	0.96
DEOGEN2	Uncertain	0.52	D;.;.;T;T;T;T;.;T;.;.;.
Eigen	Benign	0.074
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;T;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.3	N;N;N;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.20	T;T;T;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.48	T;T;T;.;.;.;.;.;.;.;.;.
Polyphen		0.91	P;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.55
MutPred		0.55		Gain of methylation at Q113 (P = 0.0193);Gain of methylation at Q113 (P = 0.0193);Gain of methylation at Q113 (P = 0.0193);.;Gain of methylation at Q113 (P = 0.0193);.;Gain of methylation at Q113 (P = 0.0193);.;.;.;.;.;
MVP		0.83
MPC		0.40
ClinPred		0.82	D
GERP RS		5.5
Varity_R		0.37
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.35		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553638735; hg19: chr3-49458926;