rs6668344

Variant names:

• chr1-236838026-C-T
• rs6668344
• NM_000254.3:c.1330-388C>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.1330-388C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,914 control chromosomes in the GnomAD database, including 11,109 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 0.38 (11109 hom., cov: 32)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 6 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.1330-388C>T		intron_variant	Intron 14 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.1330-388C>T		intron_variant	Intron 14 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.73-388C>T		intron_variant	Intron 1 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.376 AC: 57011 AN: 151796 Hom.: 11101 Cov.: 32

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.414

Gnomad OTH AF: 0.373

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

GnomAD4 genome AF: 0.376 AC: 57055 AN: 151914 Hom.: 11109 Cov.: 32 AF XY: 0.377 AC XY: 27998 AN XY: 74230

African (AFR) AF: 0.281 AC: 11636 AN: 41406

American (AMR) AF: 0.421 AC: 6422 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1110 AN: 3466

East Asian (EAS) AF: 0.435 AC: 2248 AN: 5162

South Asian (SAS) AF: 0.298 AC: 1438 AN: 4818

European-Finnish (FIN) AF: 0.447 AC: 4704 AN: 10514

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.413 AC: 28099 AN: 67964

Other (OTH) AF: 0.369 AC: 777 AN: 2106

Alfa AF: 0.395 Hom.: 2827

Bravo AF: 0.373

Asia WGS AF: 0.361 AC: 1255 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.25
PhyloP100		0.037
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: rs6668344; hg19: chr1-237001326;