NM_005957.5:c.*4076_*4077delAA

Variant names:

• chr1-11786602-ATT-A
• rs55780505
• NM_005957.5:c.*4076_*4077delAA

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_005957.5(MTHFR):c.*4076_*4077delAA variant causes a 3 prime UTR change. The variant allele was found at a cumulative frequency of 0.0000563 (AC=8) in the gnomAD database across 142,214 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000809. 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 0.000056 (0 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 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000809 — very rare for AR gene (threshold 0.001) — PM2 moderate.

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.*4076_*4077delAA	3_prime_UTR	Exon 12 of 12	Prot: NP_005948.3
	C1orf167 NM_001010881.2	MANE Select	c.3568-768_3568-767delTT	intron	Intron 16 of 20	Prot: NP_001010881.1 UniProt:
	MTHFR NM_001330358.2		c.*4076_*4077delAA	3_prime_UTR	Exon 12 of 12	Prot: NP_001317287.1 UniProt:

MTHFR NM_005957.5

MANE Select

HGVSc / HGVSpc.*4076_*4077delAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: NP_005948.3

C1orf167 NM_001010881.2

MANE Select

HGVSc / HGVSpc.3568-768_3568-767delTT

Exon rankIntron 16 of 20

intron

Prot: NP_001010881.1UniProt: Q5SNV9-1

MTHFR NM_001330358.2

HGVSc / HGVSpc.*4076_*4077delAA

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.*4076_*4077delAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365775.3 UniProt:
	MTHFR ENST00000376592.6	TSL:1	c.*4076_*4077delAA	3_prime_UTR	Exon 12 of 12	Prot: ENSP00000365777.1 UniProt:
	C1orf167 ENST00000688073.1	MANE Select	c.3568-768_3568-767delTT	intron	Intron 16 of 20	Prot: ENSP00000510540.1 UniProt:

MTHFR ENST00000376590.9

TSL:1MANE Select

HGVSc / HGVSpc.*4076_*4077delAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365775.3UniProt: P42898-1

MTHFR ENST00000376592.6

TSL:1

HGVSc / HGVSpc.*4076_*4077delAA

Exon rankExon 12 of 12

3_prime_UTR

Prot: ENSP00000365777.1UniProt: P42898-1

C1orf167 ENST00000688073.1

MANE Select

HGVSc / HGVSpc.3568-768_3568-767delTT

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: 0.0000633	AC:9	Hom:0	AN:142184	Cov:0
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:4	Cov:
GnomAD4 genome	AF: 0.0000563	AC:8	Hom:0	AN:142214	Cov:0
TOPMed (Bravo)	AF: 0.000249	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:600	AN:5410	Cov:

Showing 5 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