rs2275566

Positions:

• chr1-236885262-G-A
• chr1-236885262-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.2775+43G>A		intron_variant		ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2775+43G>A		intron_variant		1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1437+43G>A		intron_variant		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

GnomAD3 exomes AF: 0.673 AC: 163782 AN: 243312 Hom.: 55973 AF XY: 0.667 AC XY: 88091 AN XY: 131998

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 SAS exome AF: 0.719

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

Gnomad4 AFR exome AF: 0.904

Gnomad4 AMR exome AF: 0.686

Gnomad4 ASJ exome AF: 0.513

Gnomad4 EAS exome AF: 0.842

Gnomad4 SAS exome AF: 0.716

Gnomad4 FIN exome AF: 0.656

Gnomad4 NFE exome AF: 0.621

Gnomad4 OTH exome AF: 0.649

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

Gnomad4 AFR AF: 0.894

Gnomad4 AMR AF: 0.672

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.814

Gnomad4 SAS AF: 0.726

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.631

Gnomad4 OTH AF: 0.675

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.069
DANN	Benign	0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs2275566; hg19: chr1-237048562;