rs1805087

Positions:

• chr1-236885200-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000254.3(MTR):​c.2756A>G​(p.Asp919Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,590,910 control chromosomes in the GnomAD database, including 34,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3656 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30392 hom.)
• Consequence: MTR NM_000254.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7 O:1
• Conservation: PhyloP100: 8.54

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MTR. . Gene score misZ 2.0433 (greater than the threshold 3.09). Trascript score misZ 3.2999 (greater than threshold 3.09). GenCC has associacion of gene with methylcobalamin deficiency type cblG.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0016700923).
• BP6: Variant 1-236885200-A-G is Benign according to our data. Variant chr1-236885200-A-G is described in ClinVar as [Benign]. Clinvar id is 138289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236885200-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTR	NM_000254.3	c.2756A>G	p.Asp919Gly	missense_variant	26/33	ENST00000366577.10	NP_000245.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTR	ENST00000366577.10	c.2756A>G	p.Asp919Gly	missense_variant	26/33	1	NM_000254.3	ENSP00000355536	P1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32337 AN: 152018 Hom.: 3645 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.190

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.203 AC: 50989 AN: 251124 Hom.: 5663 AF XY: 0.208 AC XY: 28257 AN XY: 135746

Gnomad AFR exome AF: 0.266

Gnomad AMR exome AF: 0.184

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.200 AC: 287192 AN: 1438774 Hom.: 30392 Cov.: 29 AF XY: 0.203 AC XY: 145505 AN XY: 717146

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.172

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.203

GnomAD4 genome AF: 0.213 AC: 32375 AN: 152136 Hom.: 3656 Cov.: 32 AF XY: 0.214 AC XY: 15932 AN XY: 74382

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.196

Gnomad4 OTH AF: 0.196

Alfa AF: 0.192 Hom.: 7497

Bravo AF: 0.209

TwinsUK AF: 0.203 AC: 752

ALSPAC AF: 0.199 AC: 768

ESP6500AA AF: 0.264 AC: 1164

ESP6500EA AF: 0.198 AC: 1702

ExAC AF: 0.209 AC: 25325

Asia WGS AF: 0.218 AC: 758 AN: 3478

EpiCase AF: 0.182

EpiControl AF: 0.182

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylcobalamin deficiency type cblG Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

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	Nov 29, 2023	- -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

-

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2013

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

Mar 06, 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. -

MTR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neural tube defects, folate-sensitive, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	.;D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	0.00013	P;P
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.16	.;B;.
Vest4		0.22
MPC		0.70
ClinPred		0.040	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805087; hg19: chr1-237048500; COSMIC: COSV63964936;