NM_005957.5:c.1530+2T>C

Variant names:

• chr1-11793905-A-G
• rs786204027
• NM_005957.5:c.1530+2T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_005957.5(MTHFR):​c.1530+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MTHFR NM_005957.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.74
• Publications: 2 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 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.092846274 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.2, offset of 5, new splice context is: gtgGTaggg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-11793905-A-G is Pathogenic according to our data. Variant chr1-11793905-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 187895.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.1530+2T>C		splice_donor intron	N/A	NP_005948.3
	MTHFR	NM_001330358.2		c.1653+2T>C		splice_donor intron	N/A	NP_001317287.1
	MTHFR	NM_001410750.1		c.1650+2T>C		splice_donor intron	N/A	NP_001397679.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.1530+2T>C		splice_donor intron	N/A	ENSP00000365775.3
	MTHFR	ENST00000423400.7	TSL:1	c.1650+2T>C		splice_donor intron	N/A	ENSP00000398908.3
	MTHFR	ENST00000376592.6	TSL:1	c.1530+2T>C		splice_donor intron	N/A	ENSP00000365777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449466 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719478

African (AFR) AF: 0.00 AC: 0 AN: 33328

American (AMR) AF: 0.00 AC: 0 AN: 43908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25452

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 84828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1104522

Other (OTH) AF: 0.00 AC: 0 AN: 59796

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.7
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.42		Position offset: -3
DS_DL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204027; hg19: chr1-11853962;