3-49422381-G-C

Variant names:

• chr3-49422381-G-C
• rs371656220
• NM_000481.4:c.70C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000481.4(AMT):​c.70C>G​(p.Arg24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22
• Publications: 0 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]

NICN1 (HGNC:18317): (nicolin 1, tubulin polyglutamylase complex subunit) This protein encoded by this gene localizes to the nucleus and is expressed in numerous tissues including brain, testis, liver, and kidney. This refseq contains genomic sequence in its 3' UTR which is not supported by experimental evidence. Computer predictions indicate that this region of the 3' UTR contains hairpin-forming self-complementary sequence which is possibly excised after transcription. This gene has a pseudogene on chromosome X. [provided by RefSeq, Jul 2008]

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	NM_000481.4	MANE Select	c.70C>G	p.Arg24Gly	missense	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2452C>G		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_001164712.2		c.70C>G	p.Arg24Gly	missense	Exon 1 of 10	NP_001158184.1	P48728-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.70C>G	p.Arg24Gly	missense	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.70C>G	p.Arg24Gly	missense	Exon 1 of 10	ENSP00000378747.2	P48728-4
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2452C>G		3_prime_UTR	Exon 6 of 6	ENSP00000273598.4	Q9BSH3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.096	T
Polyphen		0.39	B
Vest4		0.67
MutPred		0.65		Loss of helix (P = 0.028)
MVP		0.90
MPC		0.34
ClinPred		0.46	T
GERP RS		3.6
PromoterAI		-0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.090
gMVP		0.52
Mutation Taster		=92/8	polymorphism

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: rs371656220; hg19: chr3-49459814;