3-49416844-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000481.4(AMT):c.*696C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 454,902 control chromosomes in the GnomAD database, including 20,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6707 hom., cov: 31)
  • Exomes 𝑓: 0.28 (13673 hom.)
• Consequence: AMT NM_000481.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-49416844-G-A is Benign according to our data. Variant chr3-49416844-G-A is described in ClinVar as [Benign]. Clinvar id is 346021.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMT	NM_000481.4	c.*696C>T		3_prime_UTR_variant	9/9	ENST00000273588.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMT	ENST00000273588.9	c.*696C>T		3_prime_UTR_variant	9/9	1	NM_000481.4	P1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43250 AN: 151730 Hom.: 6702 Cov.: 31

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0585

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.292

GnomAD3 exomes AF: 0.264 AC: 34458 AN: 130456 Hom.: 5493 AF XY: 0.266 AC XY: 18956 AN XY: 71208

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.459

Gnomad EAS exome AF: 0.0528

Gnomad SAS exome AF: 0.240

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.313

Gnomad OTH exome AF: 0.300

GnomAD4 exome AF: 0.285 AC: 86290 AN: 303054 Hom.: 13673 Cov.: 0 AF XY: 0.282 AC XY: 48638 AN XY: 172610

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.0548

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.308

GnomAD4 genome AF: 0.285 AC: 43272 AN: 151848 Hom.: 6707 Cov.: 31 AF XY: 0.288 AC XY: 21360 AN XY: 74246

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.0589

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.306

Gnomad4 OTH AF: 0.290

Alfa AF: 0.305 Hom.: 7692

Bravo AF: 0.263

Asia WGS AF: 0.144 AC: 507 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-ketotic hyperglycinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.5
Dann	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs10640; hg19: chr3-49454277;