dbSNP rs13306561: MTHFR:c.-14+141T>C (chr1-11805747-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005957.5(MTHFR):c.-14+141T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 154,544 control chromosomes in the GnomAD database, including 2,652 homozygotes. 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 0.18 ( 2631 hom., cov: 33)

Exomes 𝑓: 0.12 ( 21 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.11

Publications

44 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

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.-14+141T>C		intron	N/A	NP_005948.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.-14+141T>C	intron	N/A	ENSP00000365775.3
MTHFR	ENST00000376486.3	TSL:1	c.-11+141T>C	intron	N/A	ENSP00000365669.3
MTHFR	ENST00000418034.1	TSL:3	c.-414T>C	5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000405082.1

Frequencies

GnomAD3 genomes

AF:

0.178

AC:

27082

AN:

152076

Hom.:

2624

Cov.:

show subpopulations

Gnomad AFR

AF:

0.252

Gnomad AMI

AF:

0.0846

Gnomad AMR

AF:

0.122

Gnomad ASJ

AF:

0.0935

Gnomad EAS

AF:

0.127

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.158

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.157

Gnomad OTH

AF:

0.155

GnomAD4 exome

AF:

0.120

AC:

283

AN:

2350

Hom.:

Cov.:

AF XY:

0.125

AC XY:

155

AN XY:

1236

show subpopulations

African (AFR)

AF:

0.200

AC:

AN:

American (AMR)

AF:

0.105

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.0574

AC:

AN:

122

East Asian (EAS)

AF:

0.0648

AC:

AN:

108

South Asian (SAS)

AF:

0.144

AC:

AN:

180

European-Finnish (FIN)

AF:

0.0682

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.125

AC:

195

AN:

1554

Other (OTH)

AF:

0.127

AC:

AN:

158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.178

AC:

27119

AN:

152194

Hom.:

2631

Cov.:

AF XY:

0.178

AC XY:

13274

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.252

AC:

10482

AN:

41530

American (AMR)

AF:

0.122

AC:

1862

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0935

AC:

324

AN:

3466

East Asian (EAS)

AF:

0.127

AC:

656

AN:

5170

South Asian (SAS)

AF:

0.200

AC:

963

AN:

4818

European-Finnish (FIN)

AF:

0.158

AC:

1681

AN:

10612

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.157

AC:

10699

AN:

67984

Other (OTH)

AF:

0.158

AC:

334

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1172

2344

3515

4687

5859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

302

604

906

1208

1510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.157

Hom.:

2788

Bravo

AF:

0.177

Asia WGS

AF:

0.171

AC:

594

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.2

(source)

DANN

Benign

0.53

PhyloP100

1.1

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over