chr1-236896996-C-A

Variant names:

• chr1-236896996-C-A
• rs41530146
• NM_000254.3:c.3599-10C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000254.3(MTR):​c.3599-10C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00356 in 1,601,734 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (57 hom.)
• Consequence: MTR NM_000254.3 intron
• Scores: Splicing: ADA: 0.0001485
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.132
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-236896996-C-A is Benign according to our data. Variant chr1-236896996-C-A is described in ClinVar as Benign. ClinVar VariationId is 296583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0114 (1739/152296) while in subpopulation AFR AF = 0.0338 (1405/41548). AF 95% confidence interval is 0.0323. There are 36 homozygotes in GnomAd4. There are 829 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTR	NM_000254.3	c.3599-10C>A		intron_variant	Intron 31 of 32	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3599-10C>A		intron_variant	Intron 31 of 32	1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2261-10C>A		intron_variant	Intron 18 of 19	1		ENSP00000355535.3

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1740 AN: 152178 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.00496 AC: 1248 AN: 251402 AF XY: 0.00432

Gnomad AFR exome AF: 0.0365

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.0252

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00273 AC: 3964 AN: 1449438 Hom.: 57 Cov.: 29 AF XY: 0.00260 AC XY: 1878 AN XY: 722106

African (AFR) AF: 0.0376 AC: 1249 AN: 33188

American (AMR) AF: 0.00349 AC: 156 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 659 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00186 AC: 160 AN: 85980

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.0357 AC: 205 AN: 5742

European-Non Finnish (NFE) AF: 0.00104 AC: 1149 AN: 1100788

Other (OTH) AF: 0.00642 AC: 385 AN: 59964

GnomAD4 genome AF: 0.0114 AC: 1739 AN: 152296 Hom.: 36 Cov.: 32 AF XY: 0.0111 AC XY: 829 AN XY: 74492

African (AFR) AF: 0.0338 AC: 1405 AN: 41548

American (AMR) AF: 0.00719 AC: 110 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 80 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.00527 Hom.: 7

Bravo AF: 0.0134

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 08, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 17, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Methylcobalamin deficiency type cblG Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.56
PhyloP100		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.12		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: rs41530146; hg19: chr1-237060296;