rs10925238

Variant names:

• chr1-236818623-C-T
• rs10925238
• NM_000254.3:c.764+2080C>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.764+2080C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 152,028 control chromosomes in the GnomAD database, including 9,927 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 0.35 (9927 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 1 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 (NFE) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.764+2080C>T		intron_variant	Intron 8 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.764+2080C>T		intron_variant	Intron 8 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52851 AN: 151908 Hom.: 9924 Cov.: 33

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.346

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

GnomAD4 genome AF: 0.348 AC: 52886 AN: 152028 Hom.: 9927 Cov.: 33 AF XY: 0.349 AC XY: 25962 AN XY: 74316

African (AFR) AF: 0.207 AC: 8571 AN: 41450

American (AMR) AF: 0.405 AC: 6199 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3468

East Asian (EAS) AF: 0.405 AC: 2096 AN: 5180

South Asian (SAS) AF: 0.303 AC: 1463 AN: 4822

European-Finnish (FIN) AF: 0.431 AC: 4541 AN: 10528

Middle Eastern (MID) AF: 0.325 AC: 95 AN: 292

European-Non Finnish (NFE) AF: 0.406 AC: 27630 AN: 67976

Other (OTH) AF: 0.343 AC: 726 AN: 2114

Alfa AF: 0.373 Hom.: 1391

Bravo AF: 0.343

Asia WGS AF: 0.347 AC: 1206 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.044
DANN	Benign	0.93
PhyloP100		-1.2
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: rs10925238; hg19: chr1-236981923;