1-11800401-C-T

Position:

• chr1-11800401-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005957.5(MTHFR):​c.476-79G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 1,064,840 control chromosomes in the GnomAD database, including 14,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1443 hom., cov: 32)
  • Exomes 𝑓: 0.16 (12706 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.240

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-11800401-C-T is Benign according to our data. Variant chr1-11800401-C-T is described in ClinVar as [Benign]. Clinvar id is 1180162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.476-79G>A		intron_variant		ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.476-79G>A		intron_variant		1	NM_005957.5	ENSP00000365775	A1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18645 AN: 152036 Hom.: 1446 Cov.: 32

Gnomad AFR AF: 0.0303

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.0977

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.160 AC: 145982 AN: 912686 Hom.: 12706 Cov.: 13 AF XY: 0.164 AC XY: 78460 AN XY: 477256

Gnomad4 AFR exome AF: 0.0269

Gnomad4 AMR exome AF: 0.0808

Gnomad4 ASJ exome AF: 0.201

Gnomad4 EAS exome AF: 0.0945

Gnomad4 SAS exome AF: 0.227

Gnomad4 FIN exome AF: 0.169

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.122 AC: 18638 AN: 152154 Hom.: 1443 Cov.: 32 AF XY: 0.123 AC XY: 9145 AN XY: 74386

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.0977

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.145

Alfa AF: 0.109 Hom.: 383

Bravo AF: 0.113

Asia WGS AF: 0.150 AC: 521 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.68

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: rs2066471; hg19: chr1-11860458; COSMIC: COSV64701666; COSMIC: COSV64701666;