NM_000254.3:c.927+404A>T

Variant names:

• chr1-236825803-A-T
• rs12096955
• NM_000254.3:c.927+404A>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.927+404A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,068 control chromosomes in the GnomAD database, including 10,079 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 (10079 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0740
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.927+404A>T		intron_variant	Intron 10 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.927+404A>T		intron_variant	Intron 10 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.349 AC: 52993 AN: 151948 Hom.: 10076 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.333

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.349 AC: 53024 AN: 152068 Hom.: 10079 Cov.: 32 AF XY: 0.350 AC XY: 26015 AN XY: 74314

African (AFR) AF: 0.199 AC: 8278 AN: 41498

American (AMR) AF: 0.406 AC: 6205 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1056 AN: 3470

East Asian (EAS) AF: 0.403 AC: 2088 AN: 5182

South Asian (SAS) AF: 0.297 AC: 1429 AN: 4814

European-Finnish (FIN) AF: 0.436 AC: 4591 AN: 10538

Middle Eastern (MID) AF: 0.332 AC: 97 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28045 AN: 67970

Other (OTH) AF: 0.342 AC: 721 AN: 2110

Alfa AF: 0.377 Hom.: 1423

Bravo AF: 0.344

Asia WGS AF: 0.346 AC: 1202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		0.074
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: rs12096955; hg19: chr1-236989103;