3-49422381-G-T

Variant names:

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

Variant summary

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

The NM_000481.4(AMT):​c.70C>A​(p.Arg24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Not reported in ClinVar
• 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>A	p.Arg24Ser	missense	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2452C>A		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_001164712.2		c.70C>A	p.Arg24Ser	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>A	p.Arg24Ser	missense	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.70C>A	p.Arg24Ser	missense	Exon 1 of 10	ENSP00000378747.2	P48728-4
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2452C>A		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: 0.00000398 AC: 1 AN: 251110 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457954 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 725308

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: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52638

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109762

Other (OTH) AF: 0.00 AC: 0 AN: 60134

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150268 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 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: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.12	T
Polyphen		0.025	B
Vest4		0.66
MutPred		0.59		Gain of loop (P = 0.0166)
MVP		0.91
MPC		0.31
ClinPred		0.35	T
GERP RS		3.6
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.090
gMVP		0.51
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -20

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

Other links and lift over

dbSNP: rs371656220; hg19: chr3-49459814;