chr1-236885376-G-T

Variant names:

• chr1-236885376-G-T
• rs2275565
• NM_000254.3:c.2775+157G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000254.3(MTR):​c.2775+157G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,086 control chromosomes in the GnomAD database, including 7,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (7550 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.749
• Publications: 45 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-236885376-G-T is Benign according to our data. Variant chr1-236885376-G-T is described in ClinVar as Benign. ClinVar VariationId is 1282022.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2775+157G>T		intron_variant	Intron 26 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2775+157G>T		intron_variant	Intron 26 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1437+157G>T		intron_variant	Intron 13 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44135 AN: 151968 Hom.: 7532 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.224

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.261

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

GnomAD4 genome AF: 0.291 AC: 44195 AN: 152086 Hom.: 7550 Cov.: 32 AF XY: 0.291 AC XY: 21673 AN XY: 74358

African (AFR) AF: 0.468 AC: 19393 AN: 41440

American (AMR) AF: 0.231 AC: 3535 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 637 AN: 3466

East Asian (EAS) AF: 0.174 AC: 899 AN: 5170

South Asian (SAS) AF: 0.405 AC: 1954 AN: 4820

European-Finnish (FIN) AF: 0.206 AC: 2177 AN: 10580

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14766 AN: 67998

Other (OTH) AF: 0.268 AC: 566 AN: 2114

Alfa AF: 0.241 Hom.: 13038

Bravo AF: 0.295

Asia WGS AF: 0.304 AC: 1058 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 01, 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	-0.81
CADD	Benign	5.9
DANN	Benign	0.70
PhyloP100		-0.75
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: rs2275565; hg19: chr1-237048676;