rs12759827

Variant names:

• chr1-236808886-A-G
• rs12759827
• NM_000254.3:c.409+113A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.409+113A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 860,214 control chromosomes in the GnomAD database, including 24,180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3384 hom., cov: 32)
  • Exomes 𝑓: 0.23 (20796 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.550
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-236808886-A-G is Benign according to our data. Variant chr1-236808886-A-G is described in ClinVar as Benign. ClinVar VariationId is 1232929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.409+113A>G		intron_variant	Intron 4 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.409+113A>G		intron_variant	Intron 4 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27790 AN: 152044 Hom.: 3384 Cov.: 32

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0626

Gnomad FIN AF: 0.193

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.226 AC: 159786 AN: 708052 Hom.: 20796 AF XY: 0.222 AC XY: 83650 AN XY: 377180

African (AFR) AF: 0.0482 AC: 887 AN: 18398

American (AMR) AF: 0.153 AC: 5724 AN: 37492

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 7169 AN: 20886

East Asian (EAS) AF: 0.000472 AC: 16 AN: 33882

South Asian (SAS) AF: 0.0821 AC: 5537 AN: 67438

European-Finnish (FIN) AF: 0.195 AC: 9792 AN: 50258

Middle Eastern (MID) AF: 0.253 AC: 1095 AN: 4328

European-Non Finnish (NFE) AF: 0.275 AC: 121250 AN: 440224

Other (OTH) AF: 0.237 AC: 8316 AN: 35146

GnomAD4 genome AF: 0.183 AC: 27784 AN: 152162 Hom.: 3384 Cov.: 32 AF XY: 0.176 AC XY: 13098 AN XY: 74410

African (AFR) AF: 0.0528 AC: 2193 AN: 41532

American (AMR) AF: 0.199 AC: 3049 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 1172 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5186

South Asian (SAS) AF: 0.0626 AC: 302 AN: 4824

European-Finnish (FIN) AF: 0.193 AC: 2042 AN: 10592

Middle Eastern (MID) AF: 0.290 AC: 84 AN: 290

European-Non Finnish (NFE) AF: 0.270 AC: 18330 AN: 67954

Other (OTH) AF: 0.216 AC: 455 AN: 2106

Alfa AF: 0.244 Hom.: 3046

Bravo AF: 0.179

Asia WGS AF: 0.0440 AC: 156 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.77
PhyloP100		-0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs12759827; hg19: chr1-236972186;