rs2229274

chr1-236826841-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.940G>A(p.Asp314Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0202 in 1,613,906 control chromosomes in the GnomAD database, including 448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (419 hom.)
• Consequence: MTR NM_000254.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.10

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=0.009125441).
• BP6: Variant 1-236826841-G-A is Benign according to our data. Variant chr1-236826841-G-A is described in ClinVar as [Benign]. Clinvar id is 296556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-236826841-G-A is described in Lovd as [Benign]. Variant chr1-236826841-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0181 (2761/152262) while in subpopulation NFE AF= 0.0235 (1599/68024). AF 95% confidence interval is 0.0225. There are 29 homozygotes in gnomad4. There are 1290 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTR	NM_000254.3	c.940G>A	p.Asp314Asn	missense_variant	11/33	ENST00000366577.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTR	ENST00000366577.10	c.940G>A	p.Asp314Asn	missense_variant	11/33	1	NM_000254.3	P1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2762 AN: 152144 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.0736

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0282

GnomAD3 exomes AF: 0.0186 AC: 4682 AN: 251400 Hom.: 61 AF XY: 0.0185 AC XY: 2508 AN XY: 135868

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0491

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00490

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0233

GnomAD4 exome AF: 0.0204 AC: 29802 AN: 1461644 Hom.: 419 Cov.: 31 AF XY: 0.0200 AC XY: 14518 AN XY: 727162

Gnomad4 AFR exome AF: 0.00950

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0529

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0221

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0181 AC: 2761 AN: 152262 Hom.: 29 Cov.: 32 AF XY: 0.0173 AC XY: 1290 AN XY: 74438

Gnomad4 AFR AF: 0.00927

Gnomad4 AMR AF: 0.0193

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0235

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0232 Hom.: 70

Bravo AF: 0.0187

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0262 AC: 225

ExAC AF: 0.0191 AC: 2317

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0258

EpiControl AF: 0.0257

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2016

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. -

Methylcobalamin deficiency type cblG Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 25, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.041
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.5	D;N
REVEL	Benign	0.12
Sift	Benign	0.20	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.23	.;B
Vest4		0.18
MPC		0.43
ClinPred		0.025	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.80

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: rs2229274; hg19: chr1-236990141;