1-236882860-A-G

Variant names:

• chr1-236882860-A-G
• rs10925257
• NM_000254.3:c.2676+2024A>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.2676+2024A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,216 control chromosomes in the GnomAD database, including 3,685 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 0.21 (3685 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.869
• Publications: 11 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 (SAS) allele frequency at 95% confidence interval = 0.303 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.2676+2024A>G		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.2523+2024A>G		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.2487+2024A>G		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.2676+2024A>G		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.2523+2024A>G		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.1338+2024A>G		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32398 AN: 152098 Hom.: 3674 Cov.: 33

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.213 AC: 32435 AN: 152216 Hom.: 3685 Cov.: 33 AF XY: 0.215 AC XY: 15963 AN XY: 74408

African (AFR) AF: 0.262 AC: 10893 AN: 41536

American (AMR) AF: 0.184 AC: 2816 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 608 AN: 3472

East Asian (EAS) AF: 0.120 AC: 622 AN: 5172

South Asian (SAS) AF: 0.316 AC: 1524 AN: 4822

European-Finnish (FIN) AF: 0.188 AC: 1993 AN: 10598

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13341 AN: 68008

Other (OTH) AF: 0.197 AC: 415 AN: 2110

Alfa AF: 0.198 Hom.: 12214

Bravo AF: 0.209

Asia WGS AF: 0.221 AC: 769 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.33
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs10925257; hg19: chr1-237046160;