Genetic Variant MTHFR:c.1530+2T>C (chr1-11793905-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

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

Variant links:

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

MTHFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.1530+2T>C		splice_donor_variant, intron_variant	Intron 9 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.1530+2T>C		splice_donor_variant, intron_variant	Intron 9 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449466

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33328

American (AMR)

AF:

0.00

AC:

AN:

43908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.00

AC:

AN:

39520

South Asian (SAS)

AF:

0.00

AC:

AN:

84828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104522

Other (OTH)

AF:

0.00

AC:

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over