1-11786602-A-ATT

Variant summary

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

The NM_005957.5(MTHFR):c.*4077_*4078insAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 141,872 control chromosomes in the GnomAD database, including 1,242 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1242 hom., cov: 0)
  • Exomes 𝑓: 0.25 (0 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 = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.*4077_*4078insAA		3_prime_UTR_variant	12/12	ENST00000376590.9
C1orf167	NM_001010881.2	c.3568-768_3568-767dup		intron_variant		ENST00000688073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.*4077_*4078insAA		3_prime_UTR_variant	12/12	1	NM_005957.5	A1
C1orf167	ENST00000688073.1	c.3568-768_3568-767dup		intron_variant			NM_001010881.2	A2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 16356 AN: 141838 Hom.: 1244 Cov.: 0

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.216

Gnomad EAS AF: 0.0867

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.205

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.115 AC: 16341 AN: 141868 Hom.: 1242 Cov.: 0 AF XY: 0.112 AC XY: 7674 AN XY: 68236

Gnomad4 AFR AF: 0.0277

Gnomad4 AMR AF: 0.0874

Gnomad4 ASJ AF: 0.216

Gnomad4 EAS AF: 0.0870

Gnomad4 SAS AF: 0.176

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.127

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;