NM_005957.5:c.*4075_*4077delAAA

Variant names:

• chr1-11786602-ATTT-A
• rs55780505
• NM_005957.5:c.*4075_*4077delAAA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019).

The NM_005957.5(MTHFR):c.*4075_*4077delAAA variant causes a 3 prime UTR change. No reliable population frequency data is available for this variant in the gnomAD database. 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 0.016 (37 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 3 publications found

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)

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease and stroke. [provided by Alliance of Genome Resources, Jun 2026]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 28 criteria.

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MTHFR NM_005957.5	MANE Select	c.*4075_*4077delAAA	3_prime_UTR	Exon 12 of 12	Prot: NP_005948.3
	C1orf167 NM_001010881.2	MANE Select	c.3568-769_3568-767delTTT	intron	Intron 16 of 20	Prot: NP_001010881.1 UniProt:
	MTHFR NM_001330358.2		c.*4075_*4077delAAA	3_prime_UTR	Exon 12 of 12	Prot: NP_001317287.1 UniProt:

MTHFR NM_005957.5

MANE Select

HGVSc / HGVSpc.*4075_*4077delAAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: NP_005948.3

C1orf167 NM_001010881.2

MANE Select

HGVSc / HGVSpc.3568-769_3568-767delTTT

Exon rankIntron 16 of 20

intron

Prot: NP_001010881.1UniProt: Q5SNV9-1

MTHFR NM_001330358.2

HGVSc / HGVSpc.*4075_*4077delAAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: NP_001317287.1UniProt: P42898-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	MTHFR ENST00000376590.9	TSL:1MANE Select	c.*4075_*4077delAAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365775.3 UniProt:
	MTHFR ENST00000376592.6	TSL:1	c.*4075_*4077delAAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365777.1 UniProt:
	C1orf167 ENST00000688073.1	MANE Select	c.3568-769_3568-767delTTT	intron	Intron 16 of 20	Prot: ENSP00000510540.1 UniProt:

MTHFR ENST00000376590.9

TSL:1MANE Select

HGVSc / HGVSpc.*4075_*4077delAAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365775.3UniProt: P42898-1

MTHFR ENST00000376592.6

TSL:1

HGVSc / HGVSpc.*4075_*4077delAAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365777.1UniProt: P42898-1

C1orf167 ENST00000688073.1

MANE Select

HGVSc / HGVSpc.3568-769_3568-767delTTT

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: 0.0158	AC:2238	Hom:37	AN:142082	Cov:0
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:4	Cov:
GnomAD4 genome Warning	AF: 0.0158	AC:2240	Hom:37	AN:142110	Cov:0
TOPMed (Bravo)	AF: 0.0454	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0264	AC:143	Hom:600	AN:5410	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0714	AC:6	Hom:0	AN:84	Cov:
Turkish Variome	AF: 0.0162	AC:21	Hom:0	AN:1296	Cov:

Showing 7 sources

ClinVar

Not reported in ClinVar

Computational Scores

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

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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.

Other links and lift over

dbSNP: rs55780505;

hg19: chr1-11846659;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar