rs3834043

chr1-11805759-GC-Gchr1-11805759-GC-GCCchr1-11805759-GC-GCCCchr1-11805759-GC-GCCCC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005957.5(MTHFR):c.-14+128del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 155,908 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0018 (273/152006) while in subpopulation NFE AF= 0.00274 (186/67924). AF 95% confidence interval is 0.00242. There are 2 homozygotes in gnomad4. There are 139 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.-14+128del		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.-14+128del		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 273 AN: 151888 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00454

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00274

Gnomad OTH AF: 0.000961

GnomAD4 exome AF: 0.00154 AC: 6 AN: 3902 Hom.: 0 Cov.: 0 AF XY: 0.000504 AC XY: 1 AN XY: 1984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00180 AC: 273 AN: 152006 Hom.: 2 Cov.: 31 AF XY: 0.00187 AC XY: 139 AN XY: 74322

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00454

Gnomad4 NFE AF: 0.00274

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00104 Hom.: 38

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3834043; hg19: chr1-11865816;