dbSNP rs17375901: MTHFR:c.1531-80G>A (chr1-11792459-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005957.5(MTHFR):c.1531-80G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 996,390 control chromosomes in the GnomAD database, including 1,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.046 ( 209 hom., cov: 33)

Exomes 𝑓: 0.050 ( 1273 hom. )

Consequence

MTHFR
NM_005957.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.144

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 1-11792459-C-T is Benign according to our data. Variant chr1-11792459-C-T is described in ClinVar as [Benign]. Clinvar id is 1233971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11792459-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.1531-80G>A		intron_variant	Intron 9 of 11	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9 link	c.1531-80G>A		intron_variant	Intron 9 of 11	1	NM_005957.5	ENSP00000365775.3		P42898-1

Frequencies

GnomAD3 genomes

AF:

0.0457

AC:

6961

AN:

152216

Hom.:

209

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0272

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0430

Gnomad FIN

AF:

0.113

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0579

Gnomad OTH

AF:

0.0315

GnomAD4 exome

AF:

0.0495

AC:

41801

AN:

844056

Hom.:

1273

AF XY:

0.0497

AC XY:

22066

AN XY:

444250

show subpopulations

Gnomad4 AFR exome

AF:

0.0280

Gnomad4 AMR exome

AF:

0.0192

Gnomad4 ASJ exome

AF:

0.0153

Gnomad4 EAS exome

AF:

0.000136

Gnomad4 SAS exome

AF:

0.0446

Gnomad4 FIN exome

AF:

0.0945

Gnomad4 NFE exome

AF:

0.0550

Gnomad4 OTH exome

AF:

0.0446

GnomAD4 genome

AF:

0.0457

AC:

6961

AN:

152334

Hom.:

209

Cov.:

AF XY:

0.0475

AC XY:

3539

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0272

Gnomad4 AMR

AF:

0.0212

Gnomad4 ASJ

AF:

0.0156

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0426

Gnomad4 FIN

AF:

0.113

Gnomad4 NFE

AF:

0.0579

Gnomad4 OTH

AF:

0.0312

Alfa

AF:

0.0541

Hom.:

133

Bravo

AF:

0.0375

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 13, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.64

DANN

Benign

0.70

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over