rs2066462

chr1-11794839-G-Achr1-11794839-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_005957.5(MTHFR):c.1056C>T(p.Ser352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,613,510 control chromosomes in the GnomAD database, including 9,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (777 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8361 hom.)
• Consequence: MTHFR NM_005957.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.561

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 1-11794839-G-A is Benign according to our data. Variant chr1-11794839-G-A is described in ClinVar as [Benign]. Clinvar id is 292238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794839-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.561 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1056C>T	p.Ser352=	synonymous_variant	7/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1056C>T	p.Ser352=	synonymous_variant	7/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.0973 AC: 14805 AN: 152120 Hom.: 776 Cov.: 32

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0674

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0826

GnomAD3 exomes AF: 0.0987 AC: 24778 AN: 251112 Hom.: 1417 AF XY: 0.101 AC XY: 13672 AN XY: 135818

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0636

Gnomad ASJ exome AF: 0.0321

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.0993

Gnomad OTH exome AF: 0.0893

GnomAD4 exome AF: 0.104 AC: 152424 AN: 1461272 Hom.: 8361 Cov.: 35 AF XY: 0.105 AC XY: 76360 AN XY: 726860

Gnomad4 AFR exome AF: 0.0802

Gnomad4 AMR exome AF: 0.0638

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.0974 AC: 14825 AN: 152238 Hom.: 777 Cov.: 32 AF XY: 0.0985 AC XY: 7329 AN XY: 74438

Gnomad4 AFR AF: 0.0884

Gnomad4 AMR AF: 0.0674

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.119

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0827

Alfa AF: 0.0943 Hom.: 325

Bravo AF: 0.0891

Asia WGS AF: 0.128 AC: 443 AN: 3478

EpiCase AF: 0.0931

EpiControl AF: 0.0872

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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, Academic Medical Center	-	- -
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. -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	9.1
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2066462; hg19: chr1-11854896; COSMIC: COSV64876888; COSMIC: COSV64876888;