3-49421943-T-C

Variant names:

• chr3-49421943-T-C
• rs1464566
• NM_000481.4:c.258+161A>G

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.258+161A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 980,648 control chromosomes in the GnomAD database, including 117,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15844 hom., cov: 32)
  • Exomes 𝑓: 0.47 (101575 hom.)
• Consequence: AMT NM_000481.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0830
• Publications: 19 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, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• 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=-0.83).
• BP6: Variant 3-49421943-T-C is Benign according to our data. Variant chr3-49421943-T-C is described in ClinVar as Benign. ClinVar VariationId is 1271985.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMT	NM_000481.4	c.258+161A>G		intron_variant	Intron 2 of 8	ENST00000273588.9	NP_000472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMT	ENST00000273588.9	c.258+161A>G		intron_variant	Intron 2 of 8	1	NM_000481.4	ENSP00000273588.3
ENSG00000283189	ENST00000636166.1	c.496-371A>G		intron_variant	Intron 4 of 10	5		ENSP00000490106.1

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66431 AN: 151912 Hom.: 15834 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.578

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.687

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.434

GnomAD4 exome AF: 0.474 AC: 392554 AN: 828618 Hom.: 101575 Cov.: 11 AF XY: 0.482 AC XY: 208941 AN XY: 433324

African (AFR) AF: 0.335 AC: 7110 AN: 21252

American (AMR) AF: 0.691 AC: 25540 AN: 36952

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 7588 AN: 21760

East Asian (EAS) AF: 0.932 AC: 32524 AN: 34890

South Asian (SAS) AF: 0.668 AC: 46961 AN: 70254

European-Finnish (FIN) AF: 0.350 AC: 12617 AN: 36000

Middle Eastern (MID) AF: 0.404 AC: 1857 AN: 4602

European-Non Finnish (NFE) AF: 0.426 AC: 240038 AN: 563112

Other (OTH) AF: 0.460 AC: 18319 AN: 39796

GnomAD4 genome AF: 0.437 AC: 66473 AN: 152030 Hom.: 15844 Cov.: 32 AF XY: 0.443 AC XY: 32926 AN XY: 74308

African (AFR) AF: 0.343 AC: 14198 AN: 41450

American (AMR) AF: 0.579 AC: 8836 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1205 AN: 3468

East Asian (EAS) AF: 0.930 AC: 4810 AN: 5174

South Asian (SAS) AF: 0.686 AC: 3301 AN: 4814

European-Finnish (FIN) AF: 0.346 AC: 3657 AN: 10570

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

European-Non Finnish (NFE) AF: 0.426 AC: 28938 AN: 67968

Other (OTH) AF: 0.440 AC: 929 AN: 2112

Alfa AF: 0.435 Hom.: 40197

Bravo AF: 0.452

Asia WGS AF: 0.777 AC: 2694 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.9
DANN	Benign	0.80
PhyloP100		0.083
PromoterAI		0.00070	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1464566; hg19: chr3-49459376;