Genetic Variant MTHFR:c.*4076_*4077dupAA (chr1-11786602-A-ATT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BS2

The NM_005957.5(MTHFR):c.*4076_*4077dupAA variant causes a 3 prime UTR change. The variant allele was found at a cumulative frequency of 0.115 (AC=16,341) in the gnomAD database across 141,868 control chromosomes, including 1,242 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.165. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1242 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 and stroke. [provided by Alliance of Genome Resources, Jun 2026]

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: Likely_benign. The variant received -4 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BS2Observed in healthy adult		≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 1242.; Very high cumulative gnomAD AC = 16341 (any gene).

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 / HGVSp	Effect	Exon rank	Protein / UniProt
MTHFR NM_005957.5	MANE Select	c.4076_4077dupAA	3_prime_UTR	Exon 12 of 12	Prot: NP_005948.3
C1orf167 NM_001010881.2	MANE Select	c.3568-768_3568-767dupTT	intron	Intron 16 of 20	Prot: NP_001010881.1 UniProt: Q5SNV9-1
MTHFR NM_001330358.2		c.4076_4077dupAA	3_prime_UTR	Exon 12 of 12	Prot: NP_001317287.1 UniProt: P42898-2

MTHFR NM_005957.5

MANE Select

HGVSc / HGVSpc.*4076_*4077dupAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: NP_005948.3

C1orf167 NM_001010881.2

MANE Select

HGVSc / HGVSpc.3568-768_3568-767dupTT

Exon rankIntron 16 of 20

intron

Prot: NP_001010881.1UniProt: Q5SNV9-1

MTHFR NM_001330358.2

HGVSc / HGVSpc.*4076_*4077dupAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: NP_001317287.1UniProt: P42898-2

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
MTHFR ENST00000376590.9	TSL:1MANE Select	c.4076_4077dupAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365775.3 UniProt: P42898-1
MTHFR ENST00000376592.6	TSL:1	c.4076_4077dupAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365777.1 UniProt: P42898-1
C1orf167 ENST00000688073.1	MANE Select	c.3568-768_3568-767dupTT	intron	Intron 16 of 20	Prot: ENSP00000510540.1 UniProt: Q5SNV9-1

MTHFR ENST00000376590.9

TSL:1MANE Select

HGVSc / HGVSpc.*4076_*4077dupAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365775.3UniProt: P42898-1

MTHFR ENST00000376592.6

TSL:1

HGVSc / HGVSpc.*4076_*4077dupAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365777.1UniProt: P42898-1

C1orf167 ENST00000688073.1

MANE Select

HGVSc / HGVSpc.3568-768_3568-767dupTT

Exon rankIntron 16 of 20

intron

Prot: ENSP00000510540.1UniProt: Q5SNV9-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.115	AC:16356	Hom:1244	AN:141838	Cov:0
GnomAD4 exome Warning	AF: 0.250	AC:1	Hom:0	AN:4	Cov:0
GnomAD4 genome	AF: 0.115	AC:16341	Hom:1242	AN:141868	Cov:0
TOPMed (Bravo) Warning	AF: 0.140	AC:37188	Hom:9699	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.119	AC:646	Hom:600	AN:5410	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
Turkish Variome	AF: 0.173	AC:224	Hom:29	AN:1296	Cov:

Showing 6 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	0.31

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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1-11786602-ATTTTTTTTT-ATTTTTTTTTTT

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

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence

Publications

Other links and lift over

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

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence