1-11786602-ATTTTTTTT-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_005957.5(MTHFR):c.*4070_*4077del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.075 in 142,226 control chromosomes in the GnomAD database, including 421 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.075 (420 hom., cov: 0)
  • Exomes 𝑓: 0.50 (1 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.308

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

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.*4070_*4077del		3_prime_UTR_variant	12/12	ENST00000376590.9
C1orf167	NM_001010881.2	c.3568-774_3568-767del		intron_variant		ENST00000688073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.*4070_*4077del		3_prime_UTR_variant	12/12	1	NM_005957.5	A1
C1orf167	ENST00000688073.1	c.3568-774_3568-767del		intron_variant			NM_001010881.2	A2

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 10649 AN: 142188 Hom.: 419 Cov.: 0

Gnomad AFR AF: 0.0823

Gnomad AMI AF: 0.0982

Gnomad AMR AF: 0.0610

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.000835

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.115

Gnomad NFE AF: 0.0824

Gnomad OTH AF: 0.0913

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 1 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.0750 AC: 10661 AN: 142222 Hom.: 420 Cov.: 0 AF XY: 0.0740 AC XY: 5069 AN XY: 68454

Gnomad4 AFR AF: 0.0826

Gnomad4 AMR AF: 0.0609

Gnomad4 ASJ AF: 0.0501

Gnomad4 EAS AF: 0.000838

Gnomad4 SAS AF: 0.0889

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.0824

Gnomad4 OTH AF: 0.0905

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

Neural tube defects, folate-sensitive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55780505; hg19: chr1-11846659;