rs2275566

Variant names:

• chr1-236885262-G-A
• rs2275566
• NM_000254.3:c.2775+43G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-236885262-G-A
• chr1-236885262-G-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.2775+43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 1,181,190 control chromosomes in the GnomAD database, including 258,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40163 hom., cov: 32)
  • Exomes 𝑓: 0.65 (218448 hom.)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 11 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 1-236885262-G-A is Benign according to our data. Variant chr1-236885262-G-A is described in ClinVar as Benign. ClinVar VariationId is 1258762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.886 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2775+43G>A		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+43G>A		intron_variant	Intron 26 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1437+43G>A		intron_variant	Intron 13 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108810 AN: 151946 Hom.: 40112 Cov.: 32

Gnomad AFR AF: 0.894

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.672

GnomAD2 exomes AF: 0.673 AC: 163782 AN: 243312 AF XY: 0.667

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.512

Gnomad EAS exome AF: 0.808

Gnomad FIN exome AF: 0.652

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.651

GnomAD4 exome AF: 0.646 AC: 665139 AN: 1029128 Hom.: 218448 Cov.: 14 AF XY: 0.648 AC XY: 344219 AN XY: 531366

African (AFR) AF: 0.904 AC: 22349 AN: 24726

American (AMR) AF: 0.686 AC: 30136 AN: 43914

Ashkenazi Jewish (ASJ) AF: 0.513 AC: 12053 AN: 23518

East Asian (EAS) AF: 0.842 AC: 31668 AN: 37624

South Asian (SAS) AF: 0.716 AC: 54929 AN: 76738

European-Finnish (FIN) AF: 0.656 AC: 33792 AN: 51474

Middle Eastern (MID) AF: 0.592 AC: 2593 AN: 4378

European-Non Finnish (NFE) AF: 0.621 AC: 447761 AN: 720746

Other (OTH) AF: 0.649 AC: 29858 AN: 46010

GnomAD4 genome AF: 0.716 AC: 108923 AN: 152062 Hom.: 40163 Cov.: 32 AF XY: 0.717 AC XY: 53293 AN XY: 74298

African (AFR) AF: 0.894 AC: 37120 AN: 41530

American (AMR) AF: 0.672 AC: 10276 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1774 AN: 3472

East Asian (EAS) AF: 0.814 AC: 4212 AN: 5172

South Asian (SAS) AF: 0.726 AC: 3487 AN: 4804

European-Finnish (FIN) AF: 0.653 AC: 6873 AN: 10532

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42856 AN: 67958

Other (OTH) AF: 0.675 AC: 1422 AN: 2106

Alfa AF: 0.663 Hom.: 9041

Bravo AF: 0.726

Asia WGS AF: 0.766 AC: 2658 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.069
DANN	Benign	0.16
PhyloP100		-1.3
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: rs2275566; hg19: chr1-237048562; COSMIC: COSV107465562;