rs10495386

Variant names:

• chr1-236869508-G-A
• rs10495386
• NM_000254.3:c.2406-4265G>A

Variant summary

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

The NM_000254.3(MTR):​c.2406-4265G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 152,180 control chromosomes in the GnomAD database, including 944 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 0.078 (944 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.868
• Publications: 5 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.2406-4265G>A		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.2253-4265G>A		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.2405+5954G>A		intron	N/A	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.2406-4265G>A		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2253-4265G>A		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1068-4265G>A		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.0782 AC: 11887 AN: 152062 Hom.: 939 Cov.: 33

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0640

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0683

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0612

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

GnomAD4 genome AF: 0.0783 AC: 11923 AN: 152180 Hom.: 944 Cov.: 33 AF XY: 0.0799 AC XY: 5944 AN XY: 74382

African (AFR) AF: 0.198 AC: 8220 AN: 41504

American (AMR) AF: 0.0643 AC: 983 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3468

East Asian (EAS) AF: 0.0679 AC: 351 AN: 5170

South Asian (SAS) AF: 0.129 AC: 624 AN: 4820

European-Finnish (FIN) AF: 0.0354 AC: 375 AN: 10602

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0163 AC: 1107 AN: 68016

Other (OTH) AF: 0.0653 AC: 138 AN: 2114

Alfa AF: 0.0518 Hom.: 158

Bravo AF: 0.0847

Asia WGS AF: 0.104 AC: 359 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.64
PhyloP100		-0.87
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: rs10495386; hg19: chr1-237032808;