rs2184226

chr1-11787379-T-C

Variant summary

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

The NM_001010881.2(C1orf167):c.3568-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0788 in 1,281,526 control chromosomes in the GnomAD database, including 4,186 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 0.071 (428 hom., cov: 33)
  • Exomes 𝑓: 0.080 (3758 hom.)
• Consequence: C1orf167 NM_001010881.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001432
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490

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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTHFR	NM_005957.5	c.*3301A>G		3_prime_UTR_variant	12/12	ENST00000376590.9
C1orf167	NM_001010881.2	c.3568-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000688073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTHFR	ENST00000376590.9	c.*3301A>G		3_prime_UTR_variant	12/12	1	NM_005957.5	A1
C1orf167	ENST00000688073.1	c.3568-9T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_001010881.2	A2

Frequencies

GnomAD3 genomes AF: 0.0713 AC: 10843 AN: 152168 Hom.: 427 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0828

Gnomad FIN AF: 0.0350

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0803

Gnomad OTH AF: 0.0871

GnomAD3 exomes AF: 0.0649 AC: 8824 AN: 135982 Hom.: 349 AF XY: 0.0683 AC XY: 5015 AN XY: 73398

Gnomad AFR exome AF: 0.0777

Gnomad AMR exome AF: 0.0458

Gnomad ASJ exome AF: 0.0588

Gnomad EAS exome AF: 0.000403

Gnomad SAS exome AF: 0.0950

Gnomad FIN exome AF: 0.0381

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0755

GnomAD4 exome AF: 0.0799 AC: 90170 AN: 1129240 Hom.: 3758 Cov.: 29 AF XY: 0.0811 AC XY: 44763 AN XY: 552138

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.0457

Gnomad4 ASJ exome AF: 0.0587

Gnomad4 EAS exome AF: 0.000245

Gnomad4 SAS exome AF: 0.0940

Gnomad4 FIN exome AF: 0.0357

Gnomad4 NFE exome AF: 0.0821

Gnomad4 OTH exome AF: 0.0773

GnomAD4 genome AF: 0.0713 AC: 10856 AN: 152286 Hom.: 428 Cov.: 33 AF XY: 0.0694 AC XY: 5170 AN XY: 74478

Gnomad4 AFR AF: 0.0786

Gnomad4 AMR AF: 0.0577

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0825

Gnomad4 FIN AF: 0.0350

Gnomad4 NFE AF: 0.0803

Gnomad4 OTH AF: 0.0862

Alfa AF: 0.0778 Hom.: 860

Bravo AF: 0.0737

Asia WGS AF: 0.0380 AC: 133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	7.2
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.15		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: rs2184226; hg19: chr1-11847436; COSMIC: COSV57174939; COSMIC: COSV57174939;