rs141919148

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6BP7BS1

The NM_000254.3(MTR):​c.2622G>A​(p.Pro874=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000533 in 1,614,130 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 1 hom. )

Consequence

MTR
NM_000254.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.833
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
Variant 1-236880782-G-A is Benign according to our data. Variant chr1-236880782-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 389998.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=-0.833 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000611 (93/152262) while in subpopulation NFE AF= 0.00109 (74/68018). AF 95% confidence interval is 0.000888. There are 0 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MTRNM_000254.3 linkuse as main transcriptc.2622G>A p.Pro874= synonymous_variant 25/33 ENST00000366577.10 NP_000245.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MTRENST00000366577.10 linkuse as main transcriptc.2622G>A p.Pro874= synonymous_variant 25/331 NM_000254.3 ENSP00000355536 P1Q99707-1

Frequencies

GnomAD3 genomes
AF:
0.000611
AC:
93
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000944
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00109
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000589
AC:
148
AN:
251480
Hom.:
0
AF XY:
0.000596
AC XY:
81
AN XY:
135914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00106
Gnomad NFE exome
AF:
0.00107
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000525
AC:
767
AN:
1461868
Hom.:
1
Cov.:
31
AF XY:
0.000557
AC XY:
405
AN XY:
727240
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00144
Gnomad4 NFE exome
AF:
0.000594
Gnomad4 OTH exome
AF:
0.000447
GnomAD4 genome
AF:
0.000611
AC:
93
AN:
152262
Hom.:
0
Cov.:
32
AF XY:
0.000564
AC XY:
42
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000944
Gnomad4 NFE
AF:
0.00109
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.000762
Hom.:
0
Bravo
AF:
0.000457
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000818
EpiControl
AF:
0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Disorders of Intracellular Cobalamin Metabolism Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxNov 29, 2017This 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
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023MTR: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
CADD
Benign
6.5
DANN
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs141919148; hg19: chr1-237044082; COSMIC: COSV63966247; API