1-236878004-A-G

Variant names:

• chr1-236878004-A-G
• rs4659740
• NM_000254.3:c.2595-2751A>G

Variant summary

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

The NM_000254.3(MTR):​c.2595-2751A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 152,032 control chromosomes in the GnomAD database, including 32,323 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 0.65 (32323 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.2595-2751A>G		intron_variant	Intron 24 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2595-2751A>G		intron_variant	Intron 24 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1257-2751A>G		intron_variant	Intron 11 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98662 AN: 151914 Hom.: 32289 Cov.: 32

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.621

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

GnomAD4 genome AF: 0.650 AC: 98749 AN: 152032 Hom.: 32323 Cov.: 32 AF XY: 0.652 AC XY: 48458 AN XY: 74318

African (AFR) AF: 0.679 AC: 28135 AN: 41456

American (AMR) AF: 0.680 AC: 10393 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1763 AN: 3464

East Asian (EAS) AF: 0.620 AC: 3204 AN: 5164

South Asian (SAS) AF: 0.706 AC: 3395 AN: 4812

European-Finnish (FIN) AF: 0.653 AC: 6895 AN: 10558

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42759 AN: 67982

Other (OTH) AF: 0.625 AC: 1319 AN: 2112

Alfa AF: 0.643 Hom.: 3917

Bravo AF: 0.654

Asia WGS AF: 0.666 AC: 2313 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.24
DANN	Benign	0.64
PhyloP100		-0.84
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: rs4659740; hg19: chr1-237041304;