rs569629260

Positions:

• chr1-11787634-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005957.5(MTHFR):​c.*3046G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 806,676 control chromosomes in the GnomAD database, including 14 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 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (11 hom.)
• Consequence: MTHFR NM_005957.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79

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]

C1orf167 (HGNC:25262): (chromosome 1 open reading frame 167) Implicated in coronary artery disease. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00266 (406/152356) while in subpopulation NFE AF= 0.00509 (346/68024). AF 95% confidence interval is 0.00464. There are 3 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.*3046G>A		3_prime_UTR_variant	12/12	ENST00000376590.9
C1orf167	NM_001010881.2	c.3673+141C>T		intron_variant		ENST00000688073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.*3046G>A		3_prime_UTR_variant	12/12	1	NM_005957.5	A1
C1orf167	ENST00000688073.1	c.3673+141C>T		intron_variant			NM_001010881.2	A2

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 408 AN: 152238 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00509

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.00452 AC: 2956 AN: 654320 Hom.: 11 Cov.: 9 AF XY: 0.00449 AC XY: 1444 AN XY: 321636

Gnomad4 AFR exome AF: 0.000377

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.000293

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00149

Gnomad4 FIN exome AF: 0.00224

Gnomad4 NFE exome AF: 0.00517

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00266 AC: 406 AN: 152356 Hom.: 3 Cov.: 33 AF XY: 0.00242 AC XY: 180 AN XY: 74502

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00509

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00503 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.46
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs569629260; hg19: chr1-11847691;