1-236891499-A-G

Variant names:

• chr1-236891499-A-G
• rs2282369
• NM_000254.3:c.3204+170A>G

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.3204+170A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 152,058 control chromosomes in the GnomAD database, including 35,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.68 (35858 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.81
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-236891499-A-G is Benign according to our data. Variant chr1-236891499-A-G is described in ClinVar as Benign. ClinVar VariationId is 1235800.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.817 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3204+170A>G		intron_variant	Intron 29 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3204+170A>G		intron_variant	Intron 29 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1866+170A>G		intron_variant	Intron 16 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.678 AC: 103069 AN: 151940 Hom.: 35812 Cov.: 32

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.800

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.592

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.638

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

GnomAD4 genome AF: 0.679 AC: 103180 AN: 152058 Hom.: 35858 Cov.: 32 AF XY: 0.679 AC XY: 50424 AN XY: 74312

African (AFR) AF: 0.825 AC: 34212 AN: 41492

American (AMR) AF: 0.638 AC: 9751 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1824 AN: 3472

East Asian (EAS) AF: 0.760 AC: 3917 AN: 5156

South Asian (SAS) AF: 0.639 AC: 3066 AN: 4796

European-Finnish (FIN) AF: 0.636 AC: 6722 AN: 10572

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41428 AN: 67970

Other (OTH) AF: 0.641 AC: 1356 AN: 2116

Alfa AF: 0.656 Hom.: 5223

Bravo AF: 0.688

Asia WGS AF: 0.696 AC: 2417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.86
CADD	Benign	0.13
DANN	Benign	0.21
PhyloP100		-1.8
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: rs2282369; hg19: chr1-237054799;