Variant rs12121543 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005957.5(MTHFR):c.1167-76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,607,144 control chromosomes in the GnomAD database, including 48,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3722 hom., cov: 32)

Exomes 𝑓: 0.24 ( 45065 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.137

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-11794614-C-A is Benign according to our data. Variant chr1-11794614-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1177041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794614-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.323 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.1167-76G>T		intron_variant		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.1167-76G>T		intron_variant		1	NM_005957.5	ENSP00000365775	A1	P42898-1

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32419

AN:

151922

Hom.:

3726

Cov.:

show subpopulations

Gnomad AFR

AF:

0.143

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.156

Gnomad ASJ

AF:

0.225

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.287

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.216

GnomAD4 exome

AF:

0.245

AC:

356202

AN:

1455104

Hom.:

45065

Cov.:

AF XY:

0.249

AC XY:

180016

AN XY:

724260

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.132

Gnomad4 ASJ exome

AF:

0.225

Gnomad4 EAS exome

AF:

0.194

Gnomad4 SAS exome

AF:

0.345

Gnomad4 FIN exome

AF:

0.272

Gnomad4 NFE exome

AF:

0.246

Gnomad4 OTH exome

AF:

0.243

GnomAD4 genome

AF:

0.213

AC:

32433

AN:

152040

Hom.:

3722

Cov.:

AF XY:

0.215

AC XY:

15992

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.144

Gnomad4 AMR

AF:

0.156

Gnomad4 ASJ

AF:

0.225

Gnomad4 EAS

AF:

0.208

Gnomad4 SAS

AF:

0.337

Gnomad4 FIN

AF:

0.287

Gnomad4 NFE

AF:

0.249

Gnomad4 OTH

AF:

0.216

Alfa

AF:

0.231

Hom.:

4334

Bravo

AF:

0.197

Asia WGS

AF:

0.257

AC:

893

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

DANN

Benign

0.75

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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