1-11802157-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005957.5(MTHFR):c.236+724A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,108 control chromosomes in the GnomAD database, including 3,491 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3491 hom., cov: 32)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.161

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.236+724A>G		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.236+724A>G		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27884 AN: 151990 Hom.: 3482 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.183 AC: 27903 AN: 152108 Hom.: 3491 Cov.: 32 AF XY: 0.189 AC XY: 14085 AN XY: 74338

Gnomad4 AFR AF: 0.0434

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.128

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.283

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.176

Alfa AF: 0.203 Hom.: 4933

Bravo AF: 0.159

Asia WGS AF: 0.348 AC: 1211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	6.5
Dann	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs9651118; hg19: chr1-11862214;