1-236824490-G-T

Variant names:

• chr1-236824490-G-T
• rs4077829
• NM_000254.3:c.865+271G>T

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.865+271G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,062 control chromosomes in the GnomAD database, including 10,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.35 (10078 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 9 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=-0.92).
• BP6: Variant 1-236824490-G-T is Benign according to our data. Variant chr1-236824490-G-T is described in ClinVar as Benign. ClinVar VariationId is 1276218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.865+271G>T		intron_variant	Intron 9 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.865+271G>T		intron_variant	Intron 9 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.350 AC: 53227 AN: 151944 Hom.: 10075 Cov.: 31

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.563

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.350 AC: 53259 AN: 152062 Hom.: 10078 Cov.: 31 AF XY: 0.351 AC XY: 26115 AN XY: 74314

African (AFR) AF: 0.207 AC: 8583 AN: 41480

American (AMR) AF: 0.407 AC: 6223 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1054 AN: 3466

East Asian (EAS) AF: 0.404 AC: 2087 AN: 5170

South Asian (SAS) AF: 0.294 AC: 1417 AN: 4818

European-Finnish (FIN) AF: 0.434 AC: 4582 AN: 10562

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27982 AN: 67970

Other (OTH) AF: 0.343 AC: 723 AN: 2110

Alfa AF: 0.356 Hom.: 2664

Bravo AF: 0.346

Asia WGS AF: 0.345 AC: 1199 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

- -

Jul 07, 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	-0.92
CADD	Benign	0.11
DANN	Benign	0.54
PhyloP100		-1.5
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: rs4077829; hg19: chr1-236987790; COSMIC: COSV107465516; COSMIC: COSV107465516;