Genetic Variant MTHFR:c.*4077dupA (chr1-11786602-A-AT) – 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.*4077dupA 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 0.0036 ( 5 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:

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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 afr. GnomAd4 allele frequency = 0.00363 (516/142196) while in subpopulation AFR AF = 0.00908 (351/38648). AF 95% confidence interval is 0.0083. There are 5 homozygotes in GnomAd4. There are 241 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.*4077dupA	3_prime_UTR	Exon 12 of 12	NP_005948.3
C1orf167	NM_001010881.2	MANE Select	c.3568-767dupT	intron	N/A	NP_001010881.1
MTHFR	NM_001330358.2		c.*4077dupA	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.*4077dupA	3_prime_UTR	Exon 12 of 12	ENSP00000365775.3
MTHFR	ENST00000376592.6	TSL:1	c.*4077dupA	3_prime_UTR	Exon 12 of 12	ENSP00000365777.1
C1orf167	ENST00000688073.1	MANE Select	c.3568-767dupT	intron	N/A	ENSP00000510540.1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

516

AN:

142166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00910

Gnomad AMI

AF:

0.0226

Gnomad AMR

AF:

0.00209

Gnomad ASJ

AF:

0.000297

Gnomad EAS

AF:

0.00125

Gnomad SAS

AF:

0.00227

Gnomad FIN

AF:

0.00175

Gnomad MID

AF:

0.0101

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00410

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:

0.00363

AC:

516

AN:

142196

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

241

AN XY:

68434

show subpopulations

African (AFR)

AF:

0.00908

AC:

351

AN:

38648

American (AMR)

AF:

0.00209

AC:

AN:

14332

Ashkenazi Jewish (ASJ)

AF:

0.000297

AC:

AN:

3370

East Asian (EAS)

AF:

0.00126

AC:

AN:

4772

South Asian (SAS)

AF:

0.00229

AC:

AN:

4376

European-Finnish (FIN)

AF:

0.00175

AC:

AN:

8018

Middle Eastern (MID)

AF:

0.0109

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00111

AC:

AN:

65552

Other (OTH)

AF:

0.00407

AC:

AN:

1968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

103

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:

0.00

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

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over