Genetic Variant MTHFR:c.*4074_*4077dupAAAA (chr1-11786602-A-ATTTT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001330358.2(MTHFR):c.*4074_*4077dupAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00047 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MTHFR
NM_001330358.2 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 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.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000471 (67/142222) while in subpopulation SAS AF = 0.00891 (39/4376). AF 95% confidence interval is 0.0067. There are 3 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330358.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFR	NM_005957.5	MANE Select	c.4074_4077dupAAAA	3_prime_UTR	Exon 12 of 12	NP_005948.3
C1orf167	NM_001010881.2	MANE Select	c.3568-770_3568-767dupTTTT	intron	N/A	NP_001010881.1
MTHFR	NM_001330358.2		c.4074_4077dupAAAA	3_prime_UTR	Exon 12 of 12	NP_001317287.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.4074_4077dupAAAA	3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
MTHFR	ENST00000376592.6	TSL:1	c.4074_4077dupAAAA	3_prime_UTR	Exon 12 of 12	ENSP00000365777.1
C1orf167	ENST00000688073.1	MANE Select	c.3568-770_3568-767dupTTTT	intron	N/A	ENSP00000510540.1

Frequencies

GnomAD3 genomes

AF:

0.000443

AC:

AN:

142192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000467

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000698

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00886

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000610

Gnomad OTH

AF:

0.000512

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

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:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.000471

AC:

AN:

142222

Hom.:

Cov.:

AF XY:

0.000687

AC XY:

AN XY:

68446

show subpopulations

African (AFR)

AF:

0.000517

AC:

AN:

38656

American (AMR)

AF:

0.0000697

AC:

AN:

14338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3370

East Asian (EAS)

AF:

0.00

AC:

AN:

4772

South Asian (SAS)

AF:

0.00891

AC:

AN:

4376

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000610

AC:

AN:

65560

Other (OTH)

AF:

0.00152

AC:

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

551

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over