rs3768139

Variant names:

• chr1-236864368-G-C
• rs3768139
• NM_000254.3:c.2405+814G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.2405+814G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 152,084 control chromosomes in the GnomAD database, including 40,403 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (40403 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.888 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.2405+814G>C		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.2252+814G>C		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.2405+814G>C		intron	N/A	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.2405+814G>C		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2252+814G>C		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1067+814G>C		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109164 AN: 151966 Hom.: 40352 Cov.: 31

Gnomad AFR AF: 0.896

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.632

Gnomad OTH AF: 0.681

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.719 AC: 109278 AN: 152084 Hom.: 40403 Cov.: 31 AF XY: 0.719 AC XY: 53478 AN XY: 74336

African (AFR) AF: 0.895 AC: 37195 AN: 41536

American (AMR) AF: 0.676 AC: 10333 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3468

East Asian (EAS) AF: 0.813 AC: 4187 AN: 5150

South Asian (SAS) AF: 0.727 AC: 3504 AN: 4822

European-Finnish (FIN) AF: 0.653 AC: 6893 AN: 10558

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.632 AC: 42952 AN: 67954

Other (OTH) AF: 0.684 AC: 1445 AN: 2112

Alfa AF: 0.683 Hom.: 4511

Bravo AF: 0.729

Asia WGS AF: 0.770 AC: 2675 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.18
DANN	Benign	0.23
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: rs3768139; hg19: chr1-237027668;