3-49422374-A-G

Variant names:

• chr3-49422374-A-G
• rs1362609880
• NM_000481.4:c.77T>C

Variant summary

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

The NM_000481.4(AMT):​c.77T>C​(p.Leu26Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L26H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• 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.77T>C	p.Leu26Pro	missense	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2459T>C		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_001164712.2		c.77T>C	p.Leu26Pro	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.77T>C	p.Leu26Pro	missense	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.77T>C	p.Leu26Pro	missense	Exon 1 of 10	ENSP00000378747.2	P48728-4
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2459T>C		3_prime_UTR	Exon 6 of 6	ENSP00000273598.4	Q9BSH3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461706 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.52
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.72		Gain of loop (P = 0.0166)
MVP		0.73
MPC		0.33
ClinPred		0.59	D
GERP RS		3.7
PromoterAI		0.012	Neutral
Varity_R		0.26
gMVP		0.48
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1362609880; hg19: chr3-49459807;