rs41530146

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

2
Splicing: ADA: 0.0001485
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.132
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
MTRNM_000254.3 linkuse as main transcriptc.3599-10C>A intron_variant ENST00000366577.10 NP_000245.2 Q99707-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTRENST00000366577.10 linkuse as main transcriptc.3599-10C>A intron_variant 1 NM_000254.3 ENSP00000355536.5 Q99707-1
MTRENST00000366576.3 linkuse as main transcriptc.2261-10C>A intron_variant 1 ENSP00000355535.3 B1ANE3

Frequencies

GnomAD3 genomes
AF:
0.0114
AC:
1740
AN:
152178
Hom.:
36
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 08, 2021- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJul 17, 2015This 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. -
Methylcobalamin deficiency type cblG Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Disorders of Intracellular Cobalamin Metabolism Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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. -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41530146; hg19: chr1-237060296; API