1-11786035-G-GTT

Variant names:

• chr1-11786035-G-GTT
• rs55740775
• NM_005957.5:c.*4643_*4644dupAA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005957.5(MTHFR):​c.*4643_*4644dupAA 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 0.0012 (0 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535
• Publications: 1 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]

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005957.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.*4643_*4644dupAA		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3567+756_3567+757dupTT		intron	N/A	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_001330358.2		c.*4643_*4644dupAA		3_prime_UTR	Exon 12 of 12	NP_001317287.1	P42898-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*4643_*4644dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376592.6	TSL:1	c.*4643_*4644dupAA		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
	C1orf167	ENST00000688073.1	MANE Select	c.3567+756_3567+757dupTT		intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 177 AN: 149284 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000865

Gnomad ASJ AF: 0.000582

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.000211

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000625

Gnomad OTH AF: 0.00196

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00119 AC: 178 AN: 149368 Hom.: 0 Cov.: 0 AF XY: 0.00133 AC XY: 97 AN XY: 72720

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00159 AC: 65 AN: 40886

American (AMR) AF: 0.000864 AC: 13 AN: 15052

Ashkenazi Jewish (ASJ) AF: 0.000582 AC: 2 AN: 3434

East Asian (EAS) AF: 0.00195 AC: 10 AN: 5134

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4726

European-Finnish (FIN) AF: 0.00423 AC: 41 AN: 9692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000625 AC: 42 AN: 67196

Other (OTH) AF: 0.00195 AC: 4 AN: 2056

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000226 Hom.: 2192

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

Splicing

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.

Other links and lift over

dbSNP: rs55740775;

hg19: chr1-11846092;