1-11802157-T-C

Variant names:

• chr1-11802157-T-C
• rs9651118
• NM_005957.5:c.236+724A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005957.5(MTHFR):​c.236+724A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.183 in 152,108 control chromosomes in the GnomAD database, including 3,491 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 0.18 (3491 hom., cov: 32)
• Consequence: MTHFR NM_005957.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.161
• Publications: 83 publications found

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]

MTHFR Gene-Disease associations (from GenCC):

• homocystinuria due to methylene tetrahydrofolate reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTHFR	NM_005957.5	c.236+724A>G		intron_variant	Intron 2 of 11	ENST00000376590.9	NP_005948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTHFR	ENST00000376590.9	c.236+724A>G		intron_variant	Intron 2 of 11	1	NM_005957.5	ENSP00000365775.3

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27884 AN: 151990 Hom.: 3482 Cov.: 32

Gnomad AFR AF: 0.0435

Gnomad AMI AF: 0.127

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.183 AC: 27903 AN: 152108 Hom.: 3491 Cov.: 32 AF XY: 0.189 AC XY: 14085 AN XY: 74338

African (AFR) AF: 0.0434 AC: 1802 AN: 41544

American (AMR) AF: 0.188 AC: 2874 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 445 AN: 3472

East Asian (EAS) AF: 0.407 AC: 2101 AN: 5160

South Asian (SAS) AF: 0.283 AC: 1365 AN: 4826

European-Finnish (FIN) AF: 0.371 AC: 3908 AN: 10544

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14892 AN: 67974

Other (OTH) AF: 0.176 AC: 371 AN: 2106

Alfa AF: 0.206 Hom.: 8078

Bravo AF: 0.159

Asia WGS AF: 0.348 AC: 1211 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.48
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9651118; hg19: chr1-11862214;