rs4855873

Variant names:

• chr3-49421681-A-C
• rs4855873
• NM_000481.4:c.259-109T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-49421681-A-C
• chr3-49421681-A-T

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.259-109T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 981,850 control chromosomes in the GnomAD database, including 118,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15845 hom., cov: 32)
  • Exomes 𝑓: 0.47 (102447 hom.)
• Consequence: AMT NM_000481.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.08
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, ClinGen
• 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=-0.72).
• BP6: Variant 3-49421681-A-C is Benign according to our data. Variant chr3-49421681-A-C is described in ClinVar as Benign. ClinVar VariationId is 1185268.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.259-109T>G		intron	N/A	NP_000472.2
	AMT	NM_001164712.2		c.259-109T>G		intron	N/A	NP_001158184.1	P48728-4
	AMT	NM_001164710.2		c.259-109T>G		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.259-109T>G		intron	N/A	ENSP00000273588.3	P48728-1
	ENSG00000283189	ENST00000636166.1	TSL:5	c.496-109T>G		intron	N/A	ENSP00000490106.1	A0A1B0GUH1
	AMT	ENST00000395338.7	TSL:1	c.259-109T>G		intron	N/A	ENSP00000378747.2	P48728-4

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66447 AN: 151868 Hom.: 15835 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.435

GnomAD4 exome AF: 0.475 AC: 393904 AN: 829864 Hom.: 102447 Cov.: 11 AF XY: 0.482 AC XY: 210521 AN XY: 436640

African (AFR) AF: 0.336 AC: 7244 AN: 21574

American (AMR) AF: 0.699 AC: 28499 AN: 40764

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 7655 AN: 21916

East Asian (EAS) AF: 0.932 AC: 34232 AN: 36724

South Asian (SAS) AF: 0.670 AC: 48440 AN: 72348

European-Finnish (FIN) AF: 0.350 AC: 15225 AN: 43462

Middle Eastern (MID) AF: 0.392 AC: 1558 AN: 3970

European-Non Finnish (NFE) AF: 0.424 AC: 232863 AN: 549386

Other (OTH) AF: 0.458 AC: 18188 AN: 39720

GnomAD4 genome AF: 0.437 AC: 66489 AN: 151986 Hom.: 15845 Cov.: 32 AF XY: 0.443 AC XY: 32946 AN XY: 74298

African (AFR) AF: 0.343 AC: 14212 AN: 41428

American (AMR) AF: 0.579 AC: 8839 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.348 AC: 1206 AN: 3470

East Asian (EAS) AF: 0.930 AC: 4813 AN: 5176

South Asian (SAS) AF: 0.685 AC: 3306 AN: 4826

European-Finnish (FIN) AF: 0.347 AC: 3662 AN: 10554

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28927 AN: 67950

Other (OTH) AF: 0.440 AC: 929 AN: 2110

Alfa AF: 0.427 Hom.: 2339

Bravo AF: 0.452

Asia WGS AF: 0.777 AC: 2694 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycine encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		1.1
PromoterAI		0.012	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: rs4855873; hg19: chr3-49459114;