NM_000254.3:c.1188+1197C>T

Variant names:

• chr1-236833275-C-T
• rs1806505
• NM_000254.3:c.1188+1197C>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.1188+1197C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,002 control chromosomes in the GnomAD database, including 9,974 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 (9974 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 7 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 = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.1188+1197C>T		intron_variant	Intron 13 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.1188+1197C>T		intron_variant	Intron 13 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52742 AN: 151884 Hom.: 9970 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.304

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.435

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.345

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

GnomAD4 genome AF: 0.347 AC: 52776 AN: 152002 Hom.: 9974 Cov.: 32 AF XY: 0.349 AC XY: 25902 AN XY: 74280

African (AFR) AF: 0.199 AC: 8242 AN: 41446

American (AMR) AF: 0.405 AC: 6189 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 1055 AN: 3470

East Asian (EAS) AF: 0.404 AC: 2091 AN: 5180

South Asian (SAS) AF: 0.295 AC: 1419 AN: 4816

European-Finnish (FIN) AF: 0.435 AC: 4581 AN: 10530

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27866 AN: 67976

Other (OTH) AF: 0.341 AC: 720 AN: 2110

Alfa AF: 0.368 Hom.: 1346

Bravo AF: 0.342

Asia WGS AF: 0.345 AC: 1198 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	2.0
DANN	Benign	0.60
PhyloP100		-1.1
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: rs1806505; hg19: chr1-236996575;