1-236895528-C-T

Variant names:

• chr1-236895528-C-T
• rs1131449
• NM_000254.3:c.3576C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000254.3(MTR):​c.3576C>T​(p.Leu1192Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,580,542 control chromosomes in the GnomAD database, including 264,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1192L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.54 (22919 hom., cov: 31)
  • Exomes 𝑓: 0.58 (241513 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.37
• Publications: 25 publications found

Genes affected

MTR (HGNC:7468): (5-methyltetrahydrofolate-homocysteine methyltransferase) This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

MTR Gene-Disease associations (from GenCC):

• methylcobalamin deficiency type cblG

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-236895528-C-T is Benign according to our data. Variant chr1-236895528-C-T is described in ClinVar as Benign. ClinVar VariationId is 138284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. 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
	MTR	NM_000254.3	MANE Select	c.3576C>T	p.Leu1192Leu	synonymous	Exon 31 of 33	NP_000245.2
	MTR	NM_001291939.1		c.3423C>T	p.Leu1141Leu	synonymous	Exon 30 of 32	NP_001278868.1
	MTR	NM_001410942.1		c.3387C>T	p.Leu1129Leu	synonymous	Exon 29 of 31	NP_001397871.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3576C>T	p.Leu1192Leu	synonymous	Exon 31 of 33	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.3423C>T	p.Leu1141Leu	synonymous	Exon 30 of 32	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.2238C>T	p.Leu746Leu	synonymous	Exon 18 of 20	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82672 AN: 151864 Hom.: 22891 Cov.: 31

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.510

GnomAD2 exomes AF: 0.576 AC: 113625 AN: 197208 AF XY: 0.577

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.467

Gnomad EAS exome AF: 0.543

Gnomad FIN exome AF: 0.630

Gnomad NFE exome AF: 0.572

Gnomad OTH exome AF: 0.569

GnomAD4 exome AF: 0.580 AC: 828591 AN: 1428560 Hom.: 241513 Cov.: 65 AF XY: 0.581 AC XY: 411013 AN XY: 707452

African (AFR) AF: 0.457 AC: 14938 AN: 32674

American (AMR) AF: 0.610 AC: 25014 AN: 41010

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 12014 AN: 25502

East Asian (EAS) AF: 0.601 AC: 22811 AN: 37926

South Asian (SAS) AF: 0.619 AC: 50496 AN: 81602

European-Finnish (FIN) AF: 0.632 AC: 32293 AN: 51058

Middle Eastern (MID) AF: 0.482 AC: 2760 AN: 5730

European-Non Finnish (NFE) AF: 0.581 AC: 635152 AN: 1094016

Other (OTH) AF: 0.561 AC: 33113 AN: 59042

GnomAD4 genome AF: 0.544 AC: 82742 AN: 151982 Hom.: 22919 Cov.: 31 AF XY: 0.549 AC XY: 40743 AN XY: 74268

African (AFR) AF: 0.456 AC: 18915 AN: 41450

American (AMR) AF: 0.561 AC: 8576 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1631 AN: 3472

East Asian (EAS) AF: 0.553 AC: 2840 AN: 5140

South Asian (SAS) AF: 0.606 AC: 2916 AN: 4810

European-Finnish (FIN) AF: 0.631 AC: 6656 AN: 10556

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.578 AC: 39309 AN: 67962

Other (OTH) AF: 0.514 AC: 1082 AN: 2104

Alfa AF: 0.558 Hom.: 30316

Bravo AF: 0.534

Asia WGS AF: 0.572 AC: 1989 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Methylcobalamin deficiency type cblG (2)
-	-	1	Disorders of Intracellular Cobalamin Metabolism (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.049
DANN	Benign	0.55
PhyloP100		-3.4
Mutation Taster		=99/1	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: rs1131449; hg19: chr1-237058828; COSMIC: COSV63964165;