rs12749581

chr1-236803548-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000254.3(MTR):c.155G>A(p.Arg52Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00622 in 1,614,150 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (46 hom.)
• Consequence: MTR NM_000254.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.78

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 where missense usually causes diseases, MTR
• BP4: Computational evidence support a benign effect (MetaRNN=0.011560053).
• BP6: Variant 1-236803548-G-A is Benign according to our data. Variant chr1-236803548-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 534573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236803548-G-A is described in Lovd as [Likely_benign]. Variant chr1-236803548-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (613/152282) while in subpopulation NFE AF= 0.00717 (488/68024). AF 95% confidence interval is 0.00665. There are 1 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.155G>A	p.Arg52Gln	missense_variant	2/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.155G>A	p.Arg52Gln	missense_variant	2/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152164 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00717

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00411 AC: 1034 AN: 251410 Hom.: 3 AF XY: 0.00407 AC XY: 553 AN XY: 135866

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00517

Gnomad NFE exome AF: 0.00678

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00645 AC: 9422 AN: 1461868 Hom.: 46 Cov.: 32 AF XY: 0.00624 AC XY: 4536 AN XY: 727230

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00584

Gnomad4 NFE exome AF: 0.00778

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152282 Hom.: 1 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74458

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00717

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00547 Hom.: 3

Bravo AF: 0.00393

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00410 AC: 498

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00485

EpiControl AF: 0.00717

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2020	This variant is associated with the following publications: (PMID: 31139930, 25533962, 29474406) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MTR: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -

Methylcobalamin deficiency type cblG Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	-0.022
Eigen_PC	Benign	0.0087
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.29	.;B
Vest4		0.17
MVP		0.37
MPC		0.50
ClinPred		0.11	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12749581; hg19: chr1-236966848; COSMIC: COSV63968759;