rs41530146

Positions:

• chr1-236896996-C-A
• chr1-236896996-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.3599-10C>A		intron_variant		ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.3599-10C>A		intron_variant		1	NM_000254.3	ENSP00000355536.5
MTR	ENST00000366576.3	c.2261-10C>A		intron_variant		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

GnomAD3 exomes AF: 0.00496 AC: 1248 AN: 251402 Hom.: 18 AF XY: 0.00432 AC XY: 587 AN XY: 135894

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 SAS exome AF: 0.00167

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

Gnomad4 AFR exome AF: 0.0376

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00642

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

Gnomad4 AFR AF: 0.0338

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00716 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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2015

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.6
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs41530146; hg19: chr1-237060296;