rs61739582

Positions:

• chr1-236897072-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.3665A>G​(p.Asn1222Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,614,034 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (89 hom.)
• Consequence: MTR NM_000254.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.04

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=0.0029565692).
• BP6: Variant 1-236897072-A-G is Benign according to our data. Variant chr1-236897072-A-G is described in ClinVar as [Benign]. Clinvar id is 296584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236897072-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.3665A>G	p.Asn1222Ser	missense_variant	32/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.3665A>G	p.Asn1222Ser	missense_variant	32/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2869 AN: 152102 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0658

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00492 AC: 1238 AN: 251458 Hom.: 43 AF XY: 0.00355 AC XY: 483 AN XY: 135910

Gnomad AFR exome AF: 0.0671

Gnomad AMR exome AF: 0.00257

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000882

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00202 AC: 2947 AN: 1461814 Hom.: 89 Cov.: 31 AF XY: 0.00178 AC XY: 1293 AN XY: 727216

Gnomad4 AFR exome AF: 0.0667

Gnomad4 AMR exome AF: 0.00322

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000719

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.0189 AC: 2874 AN: 152220 Hom.: 109 Cov.: 32 AF XY: 0.0187 AC XY: 1389 AN XY: 74436

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.00621

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00335 Hom.: 24

Bravo AF: 0.0209

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0604 AC: 266

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00626 AC: 760

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Disorders of Intracellular Cobalamin Metabolism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D;D;D
MetaRNN	Benign	0.0030	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.55	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	D;N;N
REVEL	Benign	0.23
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.0080	.;B;.
Vest4		0.22
MVP		0.70
MPC		0.33
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.75

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: rs61739582; hg19: chr1-237060372;