1-11790693-G-A

Position:

chr1-11790693-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005957.5(MTHFR):c.1958C>T(p.Thr653Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 1,614,162 control chromosomes in the GnomAD database, including 347 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 24 hom., cov: 33)

Exomes 𝑓: 0.019 ( 323 hom. )

Consequence

MTHFR
NM_005957.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.301

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003030628).

BP6

Variant 1-11790693-G-A is Benign according to our data. Variant chr1-11790693-G-A is described in ClinVar as [Benign]. Clinvar id is 281891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11790693-G-A is described in Lovd as [Benign]. Variant chr1-11790693-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0141 (2147/152310) while in subpopulation NFE AF= 0.022 (1497/68020). AF 95% confidence interval is 0.0211. There are 24 homozygotes in gnomad4. There are 988 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5 linkuse as main transcript	c.1958C>T	p.Thr653Met	missense_variant	12/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 linkuse as main transcript	c.1958C>T	p.Thr653Met	missense_variant	12/12	1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0141

AC:

2146

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0154

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00951

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0220

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0137

AC:

3432

AN:

251292

Hom.:

AF XY:

0.0137

AC XY:

1865

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.00935

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00304

Gnomad FIN exome

AF:

0.00957

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0194

AC:

28383

AN:

1461852

Hom.:

323

Cov.:

AF XY:

0.0191

AC XY:

13902

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00344

Gnomad4 AMR exome

AF:

0.0100

Gnomad4 ASJ exome

AF:

0.0204

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.00307

Gnomad4 FIN exome

AF:

0.0100

Gnomad4 NFE exome

AF:

0.0229

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0141

AC:

2147

AN:

152310

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

988

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00397

Gnomad4 AMR

AF:

0.0154

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00951

Gnomad4 NFE

AF:

0.0220

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.0211

Hom.:

Bravo

AF:

0.0144

TwinsUK

AF:

0.0205

AC:

ALSPAC

AF:

0.0244

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0265

AC:

228

ExAC

AF:

0.0138

AC:

1681

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0202

EpiControl

AF:

0.0234

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2018	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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:3

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	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

MTHFR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

1.1

DANN

Benign

0.90

DEOGEN2

Benign

0.17

T;.;.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.36

.;T;.;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.69

N;.;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.45

N;N;N;N;.;.

REVEL

Benign

0.14

Sift

Benign

0.16

T;T;T;T;.;.

Sift4G

Benign

0.096

T;T;T;T;.;.

Polyphen

0.0020

B;.;.;B;.;.

Vest4

0.037

MPC

0.27

ClinPred

0.0013

GERP RS

-3.5

Varity_R

0.016

gMVP

0.21

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