1-236896087-A-T

Variant names:

• chr1-236896087-A-T
• rs4659743
• NM_000254.3:c.3598+537A>T

Variant summary

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

The NM_000254.3(MTR):​c.3598+537A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 152,158 control chromosomes in the GnomAD database, including 40,628 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 0.72 (40628 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 8 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, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.3598+537A>T		intron	N/A	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.3445+537A>T		intron	N/A	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.3409+537A>T		intron	N/A	NP_001397871.1	A0A7P0TAJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3598+537A>T		intron	N/A	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.3445+537A>T		intron	N/A	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.2260+537A>T		intron	N/A	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109304 AN: 152040 Hom.: 40576 Cov.: 33

Gnomad AFR AF: 0.910

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.669

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.727

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.676

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

GnomAD4 genome AF: 0.719 AC: 109421 AN: 152158 Hom.: 40628 Cov.: 33 AF XY: 0.720 AC XY: 53561 AN XY: 74378

African (AFR) AF: 0.910 AC: 37785 AN: 41534

American (AMR) AF: 0.670 AC: 10239 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1854 AN: 3472

East Asian (EAS) AF: 0.816 AC: 4223 AN: 5178

South Asian (SAS) AF: 0.727 AC: 3499 AN: 4816

European-Finnish (FIN) AF: 0.652 AC: 6893 AN: 10570

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

European-Non Finnish (NFE) AF: 0.626 AC: 42584 AN: 67980

Other (OTH) AF: 0.679 AC: 1434 AN: 2112

Alfa AF: 0.683 Hom.: 4511

Bravo AF: 0.730

Asia WGS AF: 0.769 AC: 2673 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.68
PhyloP100		0.038
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4659743; hg19: chr1-237059387;