chr1-11786618-TTTTG-T

Variant names:

• chr1-11786618-TTTTG-T
• rs886045172
• NM_005957.5:c.*4058_*4061delCAAA

Variant summary

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

The NM_005957.5(MTHFR):​c.*4058_*4061delCAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000090 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.748
• Publications: 0 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.*4058_*4061delCAAA		3_prime_UTR	Exon 12 of 12	NP_005948.3
	C1orf167	NM_001010881.2	MANE Select	c.3568-768_3568-765delTTGT		intron	N/A	NP_001010881.1	Q5SNV9-1
	MTHFR	NM_001330358.2		c.*4058_*4061delCAAA		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.*4058_*4061delCAAA		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3	P42898-1
	MTHFR	ENST00000376592.6	TSL:1	c.*4058_*4061delCAAA		3_prime_UTR	Exon 12 of 12	ENSP00000365777.1	P42898-1
	C1orf167	ENST00000688073.1	MANE Select	c.3568-768_3568-765delTTGT		intron	N/A	ENSP00000510540.1	Q5SNV9-1

Frequencies

GnomAD3 genomes AF: 0.0000896 AC: 10 AN: 111598 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.0000956

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000780

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16

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) AF: 0.00 AC: 0 AN: 24

Other (OTH) AC: 0 AN: 0

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000896 AC: 10 AN: 111598 Hom.: 0 Cov.: 25 AF XY: 0.0000932 AC XY: 5 AN XY: 53676

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

African (AFR) AF: 0.0000956 AC: 3 AN: 31394

American (AMR) AF: 0.000197 AC: 2 AN: 10152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2562

East Asian (EAS) AF: 0.00 AC: 0 AN: 3316

South Asian (SAS) AF: 0.00 AC: 0 AN: 3628

European-Finnish (FIN) AF: 0.000146 AC: 1 AN: 6832

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000780 AC: 4 AN: 51280

Other (OTH) AF: 0.00 AC: 0 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000482962), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000307 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neural tube defects, folate-sensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886045172; hg19: chr1-11846675;