3-49417897-C-T

Variant names:

• chr3-49417897-C-T
• rs11715915
• NM_000481.4:c.954G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000481.4(AMT):​c.954G>A​(p.Arg318Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,613,826 control chromosomes in the GnomAD database, including 75,268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6559 hom., cov: 31)
  • Exomes 𝑓: 0.30 (68709 hom.)
• Consequence: AMT NM_000481.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.891
• Publications: 80 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.047).
• BP6: Variant 3-49417897-C-T is Benign according to our data. Variant chr3-49417897-C-T is described in ClinVar as Benign. ClinVar VariationId is 256240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.891 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 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.954G>A	p.Arg318Arg	synonymous	Exon 8 of 9	NP_000472.2
	AMT	NM_001164712.2		c.954G>A	p.Arg318Arg	synonymous	Exon 8 of 10	NP_001158184.1
	AMT	NM_001164710.2		c.822G>A	p.Arg274Arg	synonymous	Exon 7 of 8	NP_001158182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AMT	ENST00000273588.9	TSL:1 MANE Select	c.954G>A	p.Arg318Arg	synonymous	Exon 8 of 9	ENSP00000273588.3
	ENSG00000283189	ENST00000636166.1	TSL:5	c.1191G>A	p.Arg397Arg	synonymous	Exon 10 of 11	ENSP00000490106.1
	AMT	ENST00000395338.7	TSL:1	c.954G>A	p.Arg318Arg	synonymous	Exon 8 of 10	ENSP00000378747.2

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42689 AN: 151924 Hom.: 6557 Cov.: 31

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.199

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.0584

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.276 AC: 69306 AN: 251004 AF XY: 0.280

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.456

Gnomad EAS exome AF: 0.0558

Gnomad FIN exome AF: 0.465

Gnomad NFE exome AF: 0.312

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.298 AC: 435990 AN: 1461786 Hom.: 68709 Cov.: 39 AF XY: 0.297 AC XY: 216045 AN XY: 727192

African (AFR) AF: 0.235 AC: 7864 AN: 33480

American (AMR) AF: 0.161 AC: 7199 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 11886 AN: 26136

East Asian (EAS) AF: 0.0630 AC: 2502 AN: 39700

South Asian (SAS) AF: 0.243 AC: 20957 AN: 86258

European-Finnish (FIN) AF: 0.454 AC: 24219 AN: 53342

Middle Eastern (MID) AF: 0.316 AC: 1820 AN: 5768

European-Non Finnish (NFE) AF: 0.307 AC: 341434 AN: 1111996

Other (OTH) AF: 0.300 AC: 18109 AN: 60394

GnomAD4 genome AF: 0.281 AC: 42703 AN: 152040 Hom.: 6559 Cov.: 31 AF XY: 0.284 AC XY: 21086 AN XY: 74286

African (AFR) AF: 0.235 AC: 9732 AN: 41480

American (AMR) AF: 0.216 AC: 3303 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3472

East Asian (EAS) AF: 0.0587 AC: 303 AN: 5160

South Asian (SAS) AF: 0.226 AC: 1090 AN: 4824

European-Finnish (FIN) AF: 0.472 AC: 4972 AN: 10536

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20824 AN: 67966

Other (OTH) AF: 0.286 AC: 604 AN: 2110

Alfa AF: 0.293 Hom.: 21421

Bravo AF: 0.258

Asia WGS AF: 0.143 AC: 503 AN: 3478

EpiCase AF: 0.317

EpiControl AF: 0.311

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycine encephalopathy (6)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs11715915; hg19: chr3-49455330; COSMIC: COSV55533942; COSMIC: COSV55533942;