1-236799475-T-C

Variant names:

• chr1-236799475-T-C
• rs10925235
• NM_000254.3:c.34+3738T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000254.3(MTR):​c.34+3738T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 152,006 control chromosomes in the GnomAD database, including 37,198 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 0.69 (37198 hom., cov: 31)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00800
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.34+3738T>C		intron_variant	Intron 1 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.34+3738T>C		intron_variant	Intron 1 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.691 AC: 105030 AN: 151888 Hom.: 37131 Cov.: 31

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.786

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.647

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.657

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

GnomAD4 genome AF: 0.692 AC: 105162 AN: 152006 Hom.: 37198 Cov.: 31 AF XY: 0.693 AC XY: 51461 AN XY: 74284

African (AFR) AF: 0.839 AC: 34813 AN: 41496

American (AMR) AF: 0.662 AC: 10113 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1846 AN: 3470

East Asian (EAS) AF: 0.608 AC: 3140 AN: 5166

South Asian (SAS) AF: 0.716 AC: 3446 AN: 4816

European-Finnish (FIN) AF: 0.647 AC: 6804 AN: 10510

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.629 AC: 42711 AN: 67954

Other (OTH) AF: 0.660 AC: 1390 AN: 2106

Alfa AF: 0.658 Hom.: 4093

Bravo AF: 0.698

Asia WGS AF: 0.680 AC: 2364 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.3
DANN	Benign	0.49
PhyloP100		-0.0080
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: rs10925235; hg19: chr1-236962775;