NM_000481.4:c.259-247G>C

Variant names:

• chr3-49421819-C-G
• rs1464567
• NM_000481.4:c.259-247G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000481.4(AMT):​c.259-247G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 671,500 control chromosomes in the GnomAD database, including 81,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (13927 hom., cov: 31)
  • Exomes 𝑓: 0.48 (67127 hom.)
• Consequence: AMT NM_000481.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.352
• Publications: 17 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]

AMT Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)
• glycine encephalopathy 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000283189 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-49421819-C-G is Benign according to our data. Variant chr3-49421819-C-G is described in ClinVar as Benign. ClinVar VariationId is 1294488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

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.259-247G>C		intron	N/A	NP_000472.2
	AMT	NM_001164712.2		c.259-247G>C		intron	N/A	NP_001158184.1	P48728-4
	AMT	NM_001164710.2		c.259-247G>C		intron	N/A	NP_001158182.1	P48728-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.259-247G>C		intron	N/A	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.496-247G>C		intron	N/A	ENSP00000490106.1	A0A1B0GUH1
	AMT	ENST00000395338.7	TSL:1	c.259-247G>C		intron	N/A	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes AF: 0.391 AC: 59417 AN: 151894 Hom.: 13913 Cov.: 31

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.678

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.397

GnomAD4 exome AF: 0.480 AC: 249180 AN: 519488 Hom.: 67127 Cov.: 5 AF XY: 0.490 AC XY: 135645 AN XY: 277036

African (AFR) AF: 0.183 AC: 2729 AN: 14950

American (AMR) AF: 0.672 AC: 20817 AN: 30968

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 5755 AN: 16924

East Asian (EAS) AF: 0.933 AC: 29401 AN: 31528

South Asian (SAS) AF: 0.660 AC: 36337 AN: 55020

European-Finnish (FIN) AF: 0.350 AC: 10858 AN: 31002

Middle Eastern (MID) AF: 0.360 AC: 885 AN: 2456

European-Non Finnish (NFE) AF: 0.421 AC: 129647 AN: 307818

Other (OTH) AF: 0.442 AC: 12751 AN: 28822

GnomAD4 genome AF: 0.391 AC: 59445 AN: 152012 Hom.: 13927 Cov.: 31 AF XY: 0.399 AC XY: 29687 AN XY: 74312

African (AFR) AF: 0.186 AC: 7718 AN: 41474

American (AMR) AF: 0.561 AC: 8549 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3470

East Asian (EAS) AF: 0.930 AC: 4793 AN: 5156

South Asian (SAS) AF: 0.678 AC: 3259 AN: 4808

European-Finnish (FIN) AF: 0.346 AC: 3663 AN: 10580

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.425 AC: 28850 AN: 67962

Other (OTH) AF: 0.403 AC: 850 AN: 2110

Alfa AF: 0.398 Hom.: 1583

Bravo AF: 0.398

Asia WGS AF: 0.759 AC: 2633 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.1
DANN	Benign	0.70
PhyloP100		0.35
PromoterAI		0.00070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1464567; hg19: chr3-49459252;