chr1-11801196-T-G

Variant names:

• chr1-11801196-T-G
• rs786204013
• NM_005957.5:c.440A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_005957.5(MTHFR):​c.440A>C​(p.Gln147Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTHFR NM_005957.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0130
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11801196-T-G is Pathogenic according to our data. Variant chr1-11801196-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 187875.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31143996). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.440A>C	p.Gln147Pro	missense	Exon 3 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.563A>C	p.Gln188Pro	missense	Exon 3 of 12	NP_001317287.1
	MTHFR	NM_001410750.1		c.560A>C	p.Gln187Pro	missense	Exon 3 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.440A>C	p.Gln147Pro	missense	Exon 3 of 12	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.560A>C	p.Gln187Pro	missense	Exon 3 of 12	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.440A>C	p.Gln147Pro	missense	Exon 3 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neural tube defects, folate-sensitive Pathogenic:1

Mar 05, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Pathogenic:1

University Children's Hospital, University of Zurich

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.00020	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.013
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.47
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.071	B
Vest4		0.50
MutPred		0.57		Loss of MoRF binding (P = 0.0488)
MVP		0.93
MPC		0.45
ClinPred		0.36	T
GERP RS		1.4
Varity_R		0.82
gMVP		0.90
Mutation Taster		=9/91	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: rs786204013; hg19: chr1-11861253;