chr3-49422381-G-A

Variant names:

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

Variant summary

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

The NM_000481.4(AMT):​c.70C>T​(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,224 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R24G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• 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>T	p.Arg24Cys	missense	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2452C>T		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_001164712.2		c.70C>T	p.Arg24Cys	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>T	p.Arg24Cys	missense	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.70C>T	p.Arg24Cys	missense	Exon 1 of 10	ENSP00000378747.2	P48728-4
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2452C>T		3_prime_UTR	Exon 6 of 6	ENSP00000273598.4	Q9BSH3-1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150268 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251110 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1457956 Hom.: 0 Cov.: 36 AF XY: 0.00000965 AC XY: 7 AN XY: 725310

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39460

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86208

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000991 AC: 11 AN: 1109762

Other (OTH) AF: 0.0000166 AC: 1 AN: 60134

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150268 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73316

African (AFR) AF: 0.00 AC: 0 AN: 40940

American (AMR) AF: 0.00 AC: 0 AN: 15060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4974

South Asian (SAS) AF: 0.00 AC: 0 AN: 4618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67676

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	2	-	Glycine encephalopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.031	D
Sift4G	Uncertain	0.045	D
Polyphen		0.025	B
Vest4		0.68
MVP		0.90
MPC		0.29
ClinPred		0.32	T
GERP RS		3.6
PromoterAI		-0.073	Neutral
Varity_R		0.083
gMVP		0.49
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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;