1-11803917-C-A

Variant names:

• chr1-11803917-C-A
• rs1931226
• ENST00000376592.6:c.-801G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000376592.6(MTHFR):​c.-801G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 173,468 control chromosomes in the GnomAD database, including 12 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 0.0063 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: MTHFR ENST00000376592.6 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0850
• Publications: 7 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=-0.79).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00634 (966/152312) while in subpopulation AFR AF = 0.0226 (938/41558). AF 95% confidence interval is 0.0214. There are 12 homozygotes in GnomAd4. There are 468 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000376592.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	NM_005957.5	MANE Select	c.-13-788G>T		intron	N/A	NP_005948.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTHFR	ENST00000376592.6	TSL:1	c.-801G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	ENSP00000365777.1
	MTHFR	ENST00000431243.6	TSL:1	n.650G>T		non_coding_transcript_exon	Exon 2 of 4
	MTHFR	ENST00000376592.6	TSL:1	c.-801G>T		5_prime_UTR	Exon 2 of 12	ENSP00000365777.1

Frequencies

GnomAD3 genomes AF: 0.00631 AC: 960 AN: 152194 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000662 AC: 14 AN: 21156 Hom.: 0 Cov.: 0 AF XY: 0.000826 AC XY: 9 AN XY: 10894

African (AFR) AF: 0.0209 AC: 9 AN: 430

American (AMR) AF: 0.00 AC: 0 AN: 468

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 748

East Asian (EAS) AF: 0.00 AC: 0 AN: 480

South Asian (SAS) AF: 0.00 AC: 0 AN: 2112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 104

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14268

Other (OTH) AF: 0.00354 AC: 5 AN: 1412

GnomAD4 genome AF: 0.00634 AC: 966 AN: 152312 Hom.: 12 Cov.: 32 AF XY: 0.00628 AC XY: 468 AN XY: 74482

African (AFR) AF: 0.0226 AC: 938 AN: 41558

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00737

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.2
DANN	Benign	0.71
PhyloP100		-0.085
PromoterAI		-0.031	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1931226; hg19: chr1-11863974;