rs1252252

Variant names:

• chr1-236892702-A-T
• rs1252252
• NM_000254.3:c.3204+1373A>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.3204+1373A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 152,060 control chromosomes in the GnomAD database, including 7,252 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 0.28 (7252 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• Publications: 5 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3204+1373A>T		intron_variant	Intron 29 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3204+1373A>T		intron_variant	Intron 29 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.1866+1373A>T		intron_variant	Intron 16 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.279 AC: 42408 AN: 151942 Hom.: 7258 Cov.: 31

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.323

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

GnomAD4 genome AF: 0.279 AC: 42396 AN: 152060 Hom.: 7252 Cov.: 31 AF XY: 0.278 AC XY: 20643 AN XY: 74308

African (AFR) AF: 0.0841 AC: 3494 AN: 41530

American (AMR) AF: 0.329 AC: 5031 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.466 AC: 1619 AN: 3472

East Asian (EAS) AF: 0.184 AC: 953 AN: 5170

South Asian (SAS) AF: 0.273 AC: 1315 AN: 4818

European-Finnish (FIN) AF: 0.348 AC: 3665 AN: 10546

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25352 AN: 67932

Other (OTH) AF: 0.320 AC: 674 AN: 2108

Alfa AF: 0.316 Hom.: 1062

Bravo AF: 0.268

Asia WGS AF: 0.228 AC: 796 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.59
PhyloP100		-0.10
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: rs1252252; hg19: chr1-237056002; COSMIC: COSV107465506; COSMIC: COSV107465506;