NM_005957.5:c.4074_4077delAAAA

Variant names:

Variant summary

Our verdict is The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BA1

The NM_005957.5(MTHFR):c.*4074_*4077delAAAA variant causes a 3 prime UTR change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant allele was found at a cumulative frequency of 0.541 (AC=76,884) in the gnomAD database across 142,024 control chromosomes, including 21,334 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.738. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.54 ( 21334 hom., cov: 0)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.308

Publications

3 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: Natera, PanelApp Australia, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

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

new If you want to explore the variant's impact on the transcript NM_005957.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -8 points.

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7376 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTHFR	NM_005957.5	MANE Select	c.4074_4077delAAAA	3_prime_UTR	Exon 12 of 12	NP_005948.3
C1orf167	NM_001010881.2	MANE Select	c.3568-770_3568-767delTTTT	intron	N/A	NP_001010881.1	Q5SNV9-1
MTHFR	NM_001330358.2		c.4074_4077delAAAA	3_prime_UTR	Exon 12 of 12	NP_001317287.1	P42898-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.4074_4077delAAAA	3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
MTHFR	ENST00000376592.6	TSL:1	c.4074_4077delAAAA	3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
C1orf167	ENST00000688073.1	MANE Select	c.3568-770_3568-767delTTTT	intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

76895

AN:

141988

Hom.:

21344

Cov.:

show subpopulations

Gnomad AFR

AF:

0.387

Gnomad AMI

AF:

0.594

Gnomad AMR

AF:

0.689

Gnomad ASJ

AF:

0.626

Gnomad EAS

AF:

0.759

Gnomad SAS

AF:

0.454

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.524

Gnomad NFE

AF:

0.575

Gnomad OTH

AF:

0.556

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.541

AC:

76883

AN:

142020

Hom.:

21334

Cov.:

AF XY:

0.546

AC XY:

37285

AN XY:

68342

show subpopulations

African (AFR)

AF:

0.386

AC:

14891

AN:

38558

American (AMR)

AF:

0.690

AC:

9884

AN:

14330

Ashkenazi Jewish (ASJ)

AF:

0.626

AC:

2109

AN:

3368

East Asian (EAS)

AF:

0.758

AC:

3618

AN:

4772

South Asian (SAS)

AF:

0.453

AC:

1979

AN:

4368

European-Finnish (FIN)

AF:

0.621

AC:

4981

AN:

8024

Middle Eastern (MID)

AF:

0.522

AC:

141

AN:

270

European-Non Finnish (NFE)

AF:

0.575

AC:

37665

AN:

65480

Other (OTH)

AF:

0.554

AC:

1090

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

1457

2915

4372

5830

7287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

658

1316

1974

2632

3290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

Data not reliable, filtered out with message: SVM;DISC

AF:

0.660

AC:

174693

AN:

264690

Hom.:

65581

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.438

AC:

2368

AN:

5410

Hom.:

600

Local populations

ABraOM SABE-WGS-1171

AF:

0.692

AC:

763

AN:

1102

Hom.:

248

Turkish Variome

AF:

0.475

AC:

616

AN:

1296

Hom.:

150

UK10K

AF:

0.793

AC:

5994

AN:

7562

show subpopulations

TwinsUK

AF:

0.790

AC:

2824

AN:

3574

ALSPAC

AF:

0.793

AC:

3056

AN:

3854

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over