1-236809428-C-T

Variant names:

• chr1-236809428-C-T
• rs4659723
• NM_000254.3:c.409+655C>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.409+655C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,204 control chromosomes in the GnomAD database, including 1,123 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 0.11 (1123 hom., cov: 33)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914
• 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=-0.79).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.409+655C>T		intron_variant	Intron 4 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.409+655C>T		intron_variant	Intron 4 of 32	1	NM_000254.3	ENSP00000355536.5

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16170 AN: 152086 Hom.: 1123 Cov.: 33

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.0941

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

GnomAD4 genome AF: 0.106 AC: 16170 AN: 152204 Hom.: 1123 Cov.: 33 AF XY: 0.108 AC XY: 8002 AN XY: 74388

African (AFR) AF: 0.0271 AC: 1127 AN: 41540

American (AMR) AF: 0.0931 AC: 1424 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 367 AN: 3468

East Asian (EAS) AF: 0.0775 AC: 401 AN: 5176

South Asian (SAS) AF: 0.165 AC: 795 AN: 4816

European-Finnish (FIN) AF: 0.154 AC: 1631 AN: 10582

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10031 AN: 68012

Other (OTH) AF: 0.0978 AC: 207 AN: 2116

Alfa AF: 0.137 Hom.: 716

Bravo AF: 0.0951

Asia WGS AF: 0.115 AC: 401 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.91
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: rs4659723; hg19: chr1-236972728;