1-236896158-G-C

Variant names:

• chr1-236896158-G-C
• rs4659744
• NM_000254.3:c.3598+608G>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.3598+608G>C 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 152,072 control chromosomes in the GnomAD database, including 9,942 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 (9942 hom., cov: 34)
• Consequence: MTR NM_000254.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.740
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	NM_000254.3	MANE Select	c.3598+608G>C		intron	N/A	NP_000245.2
	MTR	NM_001291939.1		c.3445+608G>C		intron	N/A	NP_001278868.1
	MTR	NM_001410942.1		c.3409+608G>C		intron	N/A	NP_001397871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTR	ENST00000366577.10	TSL:1 MANE Select	c.3598+608G>C		intron	N/A	ENSP00000355536.5
	MTR	ENST00000535889.6	TSL:1	c.3445+608G>C		intron	N/A	ENSP00000441845.1
	MTR	ENST00000366576.3	TSL:1	c.2260+608G>C		intron	N/A	ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52684 AN: 151950 Hom.: 9940 Cov.: 34

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.343

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

GnomAD4 genome AF: 0.347 AC: 52708 AN: 152072 Hom.: 9942 Cov.: 34 AF XY: 0.348 AC XY: 25894 AN XY: 74328

African (AFR) AF: 0.196 AC: 8116 AN: 41488

American (AMR) AF: 0.400 AC: 6114 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3468

East Asian (EAS) AF: 0.436 AC: 2252 AN: 5164

South Asian (SAS) AF: 0.298 AC: 1439 AN: 4826

European-Finnish (FIN) AF: 0.445 AC: 4689 AN: 10534

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

European-Non Finnish (NFE) AF: 0.407 AC: 27645 AN: 67998

Other (OTH) AF: 0.339 AC: 718 AN: 2116

Alfa AF: 0.374 Hom.: 1391

Bravo AF: 0.341

Asia WGS AF: 0.353 AC: 1227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.5
DANN	Benign	0.62
PhyloP100		0.74
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: rs4659744; hg19: chr1-237059458;