rs4846051

Positions:

• chr1-11794400-G-A
• chr1-11794400-G-C
• chr1-11794400-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005957.5(MTHFR):​c.1305C>T​(p.Phe435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.982 in 1,613,924 control chromosomes in the GnomAD database, including 782,483 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.91 (64268 hom., cov: 31)
  • Exomes 𝑓: 0.99 (718215 hom.)
• Consequence: MTHFR NM_005957.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.648

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-11794400-G-A is Benign according to our data. Variant chr1-11794400-G-A is described in ClinVar as [Benign]. Clinvar id is 167306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794400-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.648 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1305C>T	p.Phe435=	synonymous_variant	8/12	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1305C>T	p.Phe435=	synonymous_variant	8/12	1	NM_005957.5	ENSP00000365775	A1

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138182 AN: 151946 Hom.: 64232 Cov.: 31

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.984

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.946

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.934

GnomAD3 exomes AF: 0.975 AC: 245131 AN: 251466 Hom.: 120264 AF XY: 0.981 AC XY: 133393 AN XY: 135910

Gnomad AFR exome AF: 0.678

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 0.985

Gnomad EAS exome AF: 0.999

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.984

GnomAD4 exome AF: 0.990 AC: 1447325 AN: 1461860 Hom.: 718215 Cov.: 60 AF XY: 0.991 AC XY: 720967 AN XY: 727234

Gnomad4 AFR exome AF: 0.682

Gnomad4 AMR exome AF: 0.980

Gnomad4 ASJ exome AF: 0.987

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.977

GnomAD4 genome AF: 0.909 AC: 138275 AN: 152064 Hom.: 64268 Cov.: 31 AF XY: 0.911 AC XY: 67739 AN XY: 74330

Gnomad4 AFR AF: 0.689

Gnomad4 AMR AF: 0.961

Gnomad4 ASJ AF: 0.984

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.935

Alfa AF: 0.973 Hom.: 106341

Bravo AF: 0.896

Asia WGS AF: 0.981 AC: 3411 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.998

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 15, 2023	- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.9
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4846051; hg19: chr1-11854457;