chr1-11794614-C-A

Variant names:

• chr1-11794614-C-A
• rs12121543
• NM_005957.5:c.1167-76G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.1167-76G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,607,144 control chromosomes in the GnomAD database, including 48,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3722 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45065 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.137

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-11794614-C-A is Benign according to our data. Variant chr1-11794614-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1177041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11794614-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.1167-76G>T		intron_variant	Intron 7 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.1167-76G>T		intron_variant	Intron 7 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32419 AN: 151922 Hom.: 3726 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.287

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.245 AC: 356202 AN: 1455104 Hom.: 45065 Cov.: 34 AF XY: 0.249 AC XY: 180016 AN XY: 724260

Gnomad4 AFR exome AF: 0.134 AC: 4460 AN: 33354

Gnomad4 AMR exome AF: 0.132 AC: 5906 AN: 44712

Gnomad4 ASJ exome AF: 0.225 AC: 5880 AN: 26082

Gnomad4 EAS exome AF: 0.194 AC: 7694 AN: 39632

Gnomad4 SAS exome AF: 0.345 AC: 29694 AN: 86028

Gnomad4 FIN exome AF: 0.272 AC: 14475 AN: 53170

Gnomad4 NFE exome AF: 0.246 AC: 272017 AN: 1106204

Gnomad4 Remaining exome AF: 0.243 AC: 14612 AN: 60164

GnomAD4 genome AF: 0.213 AC: 32433 AN: 152040 Hom.: 3722 Cov.: 32 AF XY: 0.215 AC XY: 15992 AN XY: 74294

Gnomad4 AFR AF: 0.144 AC: 0.143522 AN: 0.143522

Gnomad4 AMR AF: 0.156 AC: 0.156172 AN: 0.156172

Gnomad4 ASJ AF: 0.225 AC: 0.22549 AN: 0.22549

Gnomad4 EAS AF: 0.208 AC: 0.207734 AN: 0.207734

Gnomad4 SAS AF: 0.337 AC: 0.336997 AN: 0.336997

Gnomad4 FIN AF: 0.287 AC: 0.28662 AN: 0.28662

Gnomad4 NFE AF: 0.249 AC: 0.248609 AN: 0.248609

Gnomad4 OTH AF: 0.216 AC: 0.216114 AN: 0.216114

Alfa AF: 0.229 Hom.: 6604

Bravo AF: 0.197

Asia WGS AF: 0.257 AC: 893 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Homocystinuria due to methylene tetrahydrofolate reductase deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.75
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		3.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12121543; hg19: chr1-11854671; COSMIC: COSV64877122; COSMIC: COSV64877122;