rs2066470

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005957.5(MTHFR):c.117C>T(p.Pro39Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,948 control chromosomes in the GnomAD database, including 8,874 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 708 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8166 hom. )

Consequence

MTHFR
NM_005957.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -7.56

Variant links:

Genes affected

MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

MTHFR links:

MTHFR (HGNC:):

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-11803000-G-A is Benign according to our data. Variant chr1-11803000-G-A is described in ClinVar as [Benign]. Clinvar id is 292246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11803000-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-7.56 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.117C>T	p.Pro39Pro	synonymous_variant	2/12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.117C>T	p.Pro39Pro	synonymous_variant	2/12	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0930

AC:

14147

AN:

152076

Hom.:

711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.0650

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.124

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0766

GnomAD3 exomes

AF:

0.0976

AC:

24504

AN:

251096

Hom.:

1383

AF XY:

0.0997

AC XY:

13531

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.0752

Gnomad AMR exome

AF:

0.0622

Gnomad ASJ exome

AF:

0.0339

Gnomad EAS exome

AF:

0.122

Gnomad SAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.0977

Gnomad OTH exome

AF:

0.0869

GnomAD4 exome

AF:

0.103

AC:

151010

AN:

1461754

Hom.:

8166

Cov.:

AF XY:

0.104

AC XY:

75660

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.0781

Gnomad4 AMR exome

AF:

0.0623

Gnomad4 ASJ exome

AF:

0.0343

Gnomad4 EAS exome

AF:

0.109

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.104

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.0929

AC:

14144

AN:

152194

Hom.:

708

Cov.:

AF XY:

0.0944

AC XY:

7022

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0777

Gnomad4 AMR

AF:

0.0646

Gnomad4 ASJ

AF:

0.0317

Gnomad4 EAS

AF:

0.124

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.101

Gnomad4 OTH

AF:

0.0768

Alfa

AF:

0.0922

Hom.:

949

Bravo

AF:

0.0859

Asia WGS

AF:

0.127

AC:

440

AN:

3478

EpiCase

AF:

0.0915

EpiControl

AF:

0.0854

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.20

DANN

Benign

0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over