dbSNP rs41275468: MTHFR:c.*2594C>T (chr1-11788086-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_005957.5(MTHFR):c.*2594C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00394 in 1,280,862 control chromosomes in the GnomAD database, including 10 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 0.0023 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 10 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.16

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 links:

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

C1orf167 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=-0.81).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00234 (357/152378) while in subpopulation NFE AF = 0.00439 (299/68040). AF 95% confidence interval is 0.00398. There are 0 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.*2594C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6
C1orf167	NM_001010881.2 link	c.3848+39G>A		intron_variant	Intron 18 of 20	ENST00000688073.1	NP_001010881.1	Q5SNV9A2VCK6A0A8I5KXP5Q8NDG0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.*2594C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1
C1orf167	ENST00000688073.1 link	c.3848+39G>A		intron_variant	Intron 18 of 20		NM_001010881.2	ENSP00000510540.1		A0A8I5KXP5

Frequencies

GnomAD3 genomes

AF:

0.00234

AC:

356

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000747

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00439

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00214

AC:

299

AN:

139626

AF XY:

0.00221

show subpopulations

Gnomad AFR exome

AF:

0.000299

Gnomad AMR exome

AF:

0.000897

Gnomad ASJ exome

AF:

0.000144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000964

Gnomad NFE exome

AF:

0.00431

Gnomad OTH exome

AF:

0.00225

GnomAD4 exome

AF:

0.00415

AC:

4686

AN:

1128484

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

2235

AN XY:

549200

show subpopulations

African (AFR)

AF:

0.000499

AC:

AN:

24046

American (AMR)

AF:

0.00103

AC:

AN:

27116

Ashkenazi Jewish (ASJ)

AF:

0.000137

AC:

AN:

14632

East Asian (EAS)

AF:

0.0000807

AC:

AN:

12384

South Asian (SAS)

AF:

0.00111

AC:

AN:

74100

European-Finnish (FIN)

AF:

0.00116

AC:

AN:

26750

Middle Eastern (MID)

AF:

0.000233

AC:

AN:

4300

European-Non Finnish (NFE)

AF:

0.00485

AC:

4390

AN:

904714

Other (OTH)

AF:

0.00344

AC:

139

AN:

40442

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

300

601

901

1202

1502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

210

420

630

840

1050

<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:

0.00234

AC:

357

AN:

152378

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

162

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000745

AC:

AN:

41594

American (AMR)

AF:

0.000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000827

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00439

AC:

299

AN:

68040

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00230

Hom.:

Bravo

AF:

0.00234

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

1.8

(source)

DANN

Benign

0.74

PhyloP100

-1.2

Mutation Taster

=99/1

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over