dbSNP rs55763075: MTHFR:c.*303G>A (chr1-11790377-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005957.5(MTHFR):c.*303G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 652,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.425

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFR	NM_005957.5	MANE Select	c.*303G>A	3_prime_UTR	Exon 12 of 12	NP_005948.3
MTHFR	NM_001330358.2		c.*303G>A	3_prime_UTR	Exon 12 of 12	NP_001317287.1
MTHFR	NM_001410750.1		c.*303G>A	3_prime_UTR	Exon 12 of 12	NP_001397679.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*303G>A	3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
MTHFR	ENST00000423400.7	TSL:1	c.*303G>A	3_prime_UTR	Exon 12 of 12	ENSP00000398908.3
MTHFR	ENST00000376592.6	TSL:1	c.*303G>A	3_prime_UTR	Exon 12 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

500180

Hom.:

Cov.:

AF XY:

0.0000235

AC XY:

AN XY:

255566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

13732

American (AMR)

AF:

0.00

AC:

AN:

17012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13492

East Asian (EAS)

AF:

0.00

AC:

AN:

30874

South Asian (SAS)

AF:

0.00

AC:

AN:

34880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28772

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2062

European-Non Finnish (NFE)

AF:

0.0000392

AC:

AN:

331812

Other (OTH)

AF:

0.00

AC:

AN:

27544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.9

(source)

DANN

Benign

0.68

PhyloP100

-0.42

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over