rs786204007

Variant names:

• chr1-11802941-C-G
• rs786204007
• NM_005957.5:c.176G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-11802941-C-G
• chr1-11802941-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_005957.5(MTHFR):​c.176G>C​(p.Trp59Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W59C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.36
• Publications: 5 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005957.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11802941-C-G is Pathogenic according to our data. Variant chr1-11802941-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 187868.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.176G>C	p.Trp59Ser	missense	Exon 2 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.299G>C	p.Trp100Ser	missense	Exon 2 of 12	NP_001317287.1	P42898-2
	MTHFR	NM_001410750.1		c.296G>C	p.Trp99Ser	missense	Exon 2 of 12	NP_001397679.1	Q5SNW7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.176G>C	p.Trp59Ser	missense	Exon 2 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000423400.7	TSL:1	c.296G>C	p.Trp99Ser	missense	Exon 2 of 12	ENSP00000398908.3	Q5SNW7
	MTHFR	ENST00000376592.6	TSL:1	c.176G>C	p.Trp59Ser	missense	Exon 2 of 12	ENSP00000365777.1	P42898-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Homocystinuria due to methylene tetrahydrofolate reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.31	N
PhyloP100		7.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.15	T
Polyphen		0.036	B
Vest4		0.94
MutPred		0.63		Gain of disorder (P = 0.0022)
MVP		0.96
MPC		1.2
ClinPred		0.97	D
GERP RS		5.7
PromoterAI		0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204007; hg19: chr1-11862998;