1-11800786-G-A

Position:

• chr1-11800786-G-A

Variant summary

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

The NM_005957.5(MTHFR):​c.475+375C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 395,534 control chromosomes in the GnomAD database, including 5,572 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 0.17 (2454 hom., cov: 32)
  • Exomes 𝑓: 0.16 (3118 hom.)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.246

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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.475+375C>T		intron_variant		ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.475+375C>T		intron_variant		1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26326 AN: 151988 Hom.: 2450 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0942

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.156 AC: 37930 AN: 243428 Hom.: 3118 Cov.: 0 AF XY: 0.158 AC XY: 20652 AN XY: 131106

Gnomad4 AFR exome AF: 0.235

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.118

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.173 AC: 26352 AN: 152106 Hom.: 2454 Cov.: 32 AF XY: 0.174 AC XY: 12910 AN XY: 74356

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0942

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.162

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.154

Alfa AF: 0.154 Hom.: 1839

Bravo AF: 0.171

Asia WGS AF: 0.170 AC: 590 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.8
DANN	Benign	0.79

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: rs17037390; hg19: chr1-11860843;