1-236830161-G-C

Variant names:

• chr1-236830161-G-C
• rs4659725
• NM_000254.3:c.1075+893G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.1075+893G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 151,978 control chromosomes in the GnomAD database, including 41,290 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.73 (41290 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.37
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.908 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.1075+893G>C		intron_variant	Intron 12 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.1075+893G>C		intron_variant	Intron 12 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110149 AN: 151860 Hom.: 41225 Cov.: 31

Gnomad AFR AF: 0.916

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.814

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.686

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

GnomAD4 genome AF: 0.726 AC: 110279 AN: 151978 Hom.: 41290 Cov.: 31 AF XY: 0.727 AC XY: 53986 AN XY: 74256

African (AFR) AF: 0.916 AC: 38032 AN: 41512

American (AMR) AF: 0.681 AC: 10402 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1856 AN: 3468

East Asian (EAS) AF: 0.814 AC: 4205 AN: 5164

South Asian (SAS) AF: 0.728 AC: 3503 AN: 4810

European-Finnish (FIN) AF: 0.657 AC: 6896 AN: 10502

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 43028 AN: 67940

Other (OTH) AF: 0.689 AC: 1452 AN: 2106

Alfa AF: 0.563 Hom.: 1566

Bravo AF: 0.736

Asia WGS AF: 0.773 AC: 2686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.065
DANN	Benign	0.20
PhyloP100		-1.4
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: rs4659725; hg19: chr1-236993461;