1-236865264-G-T

Variant names:

• chr1-236865264-G-T
• rs3768142
• NM_000254.3:c.2405+1710G>T

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+1710G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,140 control chromosomes in the GnomAD database, including 31,671 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 0.64 (31671 hom., cov: 34)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.483
• Publications: 13 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2405+1710G>T		intron_variant	Intron 22 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2405+1710G>T		intron_variant	Intron 22 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1067+1710G>T		intron_variant	Intron 9 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97679 AN: 152022 Hom.: 31634 Cov.: 34

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.614

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

GnomAD4 genome AF: 0.643 AC: 97769 AN: 152140 Hom.: 31671 Cov.: 34 AF XY: 0.645 AC XY: 47951 AN XY: 74346

African (AFR) AF: 0.671 AC: 27844 AN: 41512

American (AMR) AF: 0.641 AC: 9801 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1765 AN: 3470

East Asian (EAS) AF: 0.610 AC: 3155 AN: 5176

South Asian (SAS) AF: 0.704 AC: 3396 AN: 4826

European-Finnish (FIN) AF: 0.653 AC: 6900 AN: 10562

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42715 AN: 67986

Other (OTH) AF: 0.618 AC: 1305 AN: 2112

Alfa AF: 0.630 Hom.: 58628

Bravo AF: 0.642

Asia WGS AF: 0.662 AC: 2300 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.8
DANN	Benign	0.69
PhyloP100		0.48
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: rs3768142; hg19: chr1-237028564;