3-49422374-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000481.4(AMT):​c.77T>A​(p.Leu26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L26L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: AMT NM_000481.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28151435).

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>A	p.Leu26His	missense	Exon 1 of 9	NP_000472.2
	NICN1	NM_032316.3	MANE Select	c.*2459T>A		3_prime_UTR	Exon 6 of 6	NP_115692.1	Q9BSH3-1
	AMT	NM_001164712.2		c.77T>A	p.Leu26His	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>A	p.Leu26His	missense	Exon 1 of 9	ENSP00000273588.3	P48728-1
	AMT	ENST00000395338.7	TSL:1	c.77T>A	p.Leu26His	missense	Exon 1 of 10	ENSP00000378747.2	P48728-4
	NICN1	ENST00000273598.8	TSL:1 MANE Select	c.*2459T>A		3_prime_UTR	Exon 6 of 6	ENSP00000273598.4	Q9BSH3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251140 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461706 Hom.: 0 Cov.: 36 AF XY: 0.00000825 AC XY: 6 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: 0.00 AC: 0 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: 0.0000135 AC: 15 AN: 1111992

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Glycine encephalopathy (1)
-	1	-	Inborn genetic diseases (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	17
DANN	Uncertain	0.97
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.90	N
REVEL	Uncertain	0.35
Sift	Benign	0.24	T
Sift4G	Benign	0.50	T
Polyphen		0.31	B
Vest4		0.19
MutPred		0.52		Gain of catalytic residue at L26 (P = 0.0028)
MVP		0.75
MPC		0.27
ClinPred		0.34	T
GERP RS		3.7
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.43
Mutation Taster		=88/12	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;