rs12030699

Variant names:

• chr1-236895448-C-T
• rs12030699
• NM_000254.3:c.3496C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-236895448-C-T
• chr1-236895448-C-A
• chr1-236895448-C-G

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.3496C>T​(p.Leu1166Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,601,094 control chromosomes in the GnomAD database, including 855 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (134 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (721 hom.)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.07
• Publications: 6 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-236895448-C-T is Benign according to our data. Variant chr1-236895448-C-T is described in ClinVar as Benign. ClinVar VariationId is 296579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.194 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.3496C>T	p.Leu1166Leu	synonymous	Exon 31 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.3343C>T	p.Leu1115Leu	synonymous	Exon 30 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.3307C>T	p.Leu1103Leu	synonymous	Exon 29 of 31	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3496C>T	p.Leu1166Leu	synonymous	Exon 31 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.3343C>T	p.Leu1115Leu	synonymous	Exon 30 of 32	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.2158C>T	p.Leu720Leu	synonymous	Exon 18 of 20	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes AF: 0.00906 AC: 1378 AN: 152168 Hom.: 136 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0189 AC: 4295 AN: 227274 AF XY: 0.0183

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00223

Gnomad EAS exome AF: 0.213

Gnomad FIN exome AF: 0.000360

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00646 AC: 9358 AN: 1448808 Hom.: 721 Cov.: 60 AF XY: 0.00659 AC XY: 4740 AN XY: 719214

African (AFR) AF: 0.00171 AC: 57 AN: 33302

American (AMR) AF: 0.00387 AC: 168 AN: 43408

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 63 AN: 25686

East Asian (EAS) AF: 0.178 AC: 6988 AN: 39206

South Asian (SAS) AF: 0.0128 AC: 1069 AN: 83836

European-Finnish (FIN) AF: 0.000497 AC: 26 AN: 52306

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5754

European-Non Finnish (NFE) AF: 0.000194 AC: 214 AN: 1105530

Other (OTH) AF: 0.0128 AC: 764 AN: 59780

GnomAD4 genome AF: 0.00901 AC: 1372 AN: 152286 Hom.: 134 Cov.: 33 AF XY: 0.00991 AC XY: 738 AN XY: 74440

African (AFR) AF: 0.00207 AC: 86 AN: 41580

American (AMR) AF: 0.00536 AC: 82 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.204 AC: 1050 AN: 5140

South Asian (SAS) AF: 0.0209 AC: 101 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68016

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00103 Hom.: 2

Bravo AF: 0.0109

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.74
PhyloP100		2.1
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: rs12030699; hg19: chr1-237058748; COSMIC: COSV63965267;