rs45622739

chr1-11790924-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005957.5(MTHFR):c.1753-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00409 in 1,600,722 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (22 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.237

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=-0.97).
• BP6: Variant 1-11790924-C-T is Benign according to our data. Variant chr1-11790924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1879073.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00356 (542/152306) while in subpopulation AMR AF= 0.00784 (120/15302). AF 95% confidence interval is 0.0067. There are 2 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. 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.1753-26G>A		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.1753-26G>A		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 542 AN: 152188 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00327 AC: 817 AN: 249930 Hom.: 3 AF XY: 0.00323 AC XY: 437 AN XY: 135192

Gnomad AFR exome AF: 0.000496

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00478

Gnomad OTH exome AF: 0.00458

GnomAD4 exome AF: 0.00414 AC: 5999 AN: 1448416 Hom.: 22 Cov.: 27 AF XY: 0.00412 AC XY: 2971 AN XY: 721272

Gnomad4 AFR exome AF: 0.000663

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00621

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.000544

Gnomad4 NFE exome AF: 0.00475

Gnomad4 OTH exome AF: 0.00403

GnomAD4 genome AF: 0.00356 AC: 542 AN: 152306 Hom.: 2 Cov.: 33 AF XY: 0.00333 AC XY: 248 AN XY: 74476

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00369 Hom.: 0

Bravo AF: 0.00403

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

MTHFR: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
Cadd	Benign	1.8
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs45622739; hg19: chr1-11850981;