1-236891269-A-C

Variant names:

• chr1-236891269-A-C
• NM_000254.3:c.3144A>C
• MTR p.Ala1048Ala

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000254.3(MTR):​c.3144A>C​(p.Ala1048Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1048A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTR NM_000254.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.12
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP7: Synonymous conserved (PhyloP=-1.12 with no splicing effect.

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.3144A>C	p.Ala1048Ala	synonymous	Exon 29 of 33	NP_000245.2	Q99707-1
	MTR	NM_001291939.1		c.2991A>C	p.Ala997Ala	synonymous	Exon 28 of 32	NP_001278868.1	Q99707-2
	MTR	NM_001410942.1		c.2955A>C	p.Ala985Ala	synonymous	Exon 27 of 31	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.3144A>C	p.Ala1048Ala	synonymous	Exon 29 of 33	ENSP00000355536.5	Q99707-1
	MTR	ENST00000535889.6	TSL:1	c.2991A>C	p.Ala997Ala	synonymous	Exon 28 of 32	ENSP00000441845.1	Q99707-2
	MTR	ENST00000366576.3	TSL:1	c.1806A>C	p.Ala602Ala	synonymous	Exon 16 of 20	ENSP00000355535.3	B1ANE3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.067
DANN	Benign	0.34
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-237054569;