rs3818762

chr1-11790946-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005957.5(MTHFR):c.1753-48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,559,624 control chromosomes in the GnomAD database, including 57,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4601 hom., cov: 33)
  • Exomes 𝑓: 0.27 (52859 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -2.26

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BP6: Variant 1-11790946-G-C is Benign according to our data. Variant chr1-11790946-G-C is described in ClinVar as [Benign]. Clinvar id is 1224887.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.1753-48C>G		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1753-48C>G		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35715 AN: 151956 Hom.: 4602 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.263

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.260 AC: 63273 AN: 243380 Hom.: 8070 AF XY: 0.272 AC XY: 35847 AN XY: 131710

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.142

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.215

Gnomad SAS exome AF: 0.414

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.274 AC: 385438 AN: 1407550 Hom.: 52859 Cov.: 25 AF XY: 0.279 AC XY: 196127 AN XY: 702690

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.262

Gnomad4 EAS exome AF: 0.208

Gnomad4 SAS exome AF: 0.420

Gnomad4 FIN exome AF: 0.283

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.235 AC: 35737 AN: 152074 Hom.: 4601 Cov.: 33 AF XY: 0.237 AC XY: 17596 AN XY: 74330

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.263

Gnomad4 EAS AF: 0.223

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.238

Alfa AF: 0.257 Hom.: 955

Bravo AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 07, 2018

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.010
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3818762; hg19: chr1-11851003; COSMIC: COSV100453746; COSMIC: COSV100453746;