Genetic Variant MTHFR:c.*4070_*4077delAAAAAAAA (chr1-11786602-ATTTTTTTT-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005957.5(MTHFR):c.*4070_*4077delAAAAAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 142,226 control chromosomes in the GnomAD database, including 421 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.075 ( 420 hom., cov: 0)

Exomes 𝑓: 0.50 ( 1 hom. )

Consequence

MTHFR
NM_005957.5 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.308

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 -8 ACMG points.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5 link	c.4070_4077delAAAAAAAA		3_prime_UTR_variant	Exon 12 of 12	ENST00000376590.9	NP_005948.3	P42898-1Q8IU67Q59GJ6
C1orf167	NM_001010881.2 link	c.3568-774_3568-767delTTTTTTTT		intron_variant	Intron 16 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.4070_4077delAAAAAAAA		3_prime_UTR_variant	Exon 12 of 12	1	NM_005957.5	ENSP00000365775.3		P42898-1
C1orf167	ENST00000688073.1 link	c.3568-774_3568-767delTTTTTTTT		intron_variant	Intron 16 of 20		NM_001010881.2	ENSP00000510540.1		A0A8I5KXP5

Frequencies

GnomAD3 genomes

AF:

0.0749

AC:

10649

AN:

142188

Hom.:

419

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0823

Gnomad AMI

AF:

0.0982

Gnomad AMR

AF:

0.0610

Gnomad ASJ

AF:

0.0501

Gnomad EAS

AF:

0.000835

Gnomad SAS

AF:

0.0889

Gnomad FIN

AF:

0.0415

Gnomad MID

AF:

0.115

Gnomad NFE

AF:

0.0824

Gnomad OTH

AF:

0.0913

GnomAD4 exome

AF:

0.500

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:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.0750

AC:

10661

AN:

142222

Hom.:

420

Cov.:

AF XY:

0.0740

AC XY:

5069

AN XY:

68454

show subpopulations

African (AFR)

AF:

0.0826

AC:

3194

AN:

38650

American (AMR)

AF:

0.0609

AC:

873

AN:

14336

Ashkenazi Jewish (ASJ)

AF:

0.0501

AC:

169

AN:

3370

East Asian (EAS)

AF:

0.000838

AC:

AN:

4772

South Asian (SAS)

AF:

0.0889

AC:

389

AN:

4378

European-Finnish (FIN)

AF:

0.0415

AC:

333

AN:

8022

Middle Eastern (MID)

AF:

0.117

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0824

AC:

5402

AN:

65568

Other (OTH)

AF:

0.0905

AC:

178

AN:

1966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.553

Heterozygous variant carriers

454

908

1362

1816

2270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0668

Hom.:

551

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Neural tube defects, folate-sensitive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Loading publications...

1-11786602-ATTTTTTTT-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over