rs786204030

Variant names:

• chr1-11791276-C-T
• rs786204030
• NM_005957.5:c.1683G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001330358.2(MTHFR):​c.1806G>A​(p.Trp602*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic,risk factor (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MTHFR NM_001330358.2 stop_gained
• Clinical Significance: Pathogenic; risk factor criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.35
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11791276-C-T is Pathogenic according to our data. Variant chr1-11791276-C-T is described in ClinVar as Pathogenic|risk_factor. ClinVar VariationId is 187898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330358.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1683G>A	p.Trp561*	stop_gained	Exon 11 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.1806G>A	p.Trp602*	stop_gained	Exon 11 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.1803G>A	p.Trp601*	stop_gained	Exon 11 of 12	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1683G>A	p.Trp561*	stop_gained	Exon 11 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1803G>A	p.Trp601*	stop_gained	Exon 11 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1683G>A	p.Trp561*	stop_gained	Exon 11 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic; risk factor

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)
1	-	-	Neural tube defects, folate-sensitive (1)
-	-	-	Neural tube defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.3
Vest4		0.93
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs786204030; hg19: chr1-11851333;