rs1537514

chr1-11788011-G-C

Variant summary

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

The NM_001010881.2(C1orf167):c.3812G>C(p.Cys1271Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,302,866 control chromosomes in the GnomAD database, including 8,183 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (861 hom., cov: 33)
  • Exomes 𝑓: 0.11 (7322 hom.)
• Consequence: C1orf167 NM_001010881.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.393

Genes affected

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

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 (MetaRNN=9.037852E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1orf167	NM_001010881.2	c.3812G>C	p.Cys1271Ser	missense_variant	18/21	ENST00000688073.1
MTHFR	NM_005957.5	c.*2669C>G		3_prime_UTR_variant	12/12	ENST00000376590.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1orf167	ENST00000688073.1	c.3812G>C	p.Cys1271Ser	missense_variant	18/21		NM_001010881.2	A2
MTHFR	ENST00000376590.9	c.*2669C>G		3_prime_UTR_variant	12/12	1	NM_005957.5	A1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15640 AN: 152150 Hom.: 860 Cov.: 33

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0688

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.0867

GnomAD3 exomes AF: 0.105 AC: 15680 AN: 149868 Hom.: 993 AF XY: 0.109 AC XY: 8756 AN XY: 80498

Gnomad AFR exome AF: 0.0928

Gnomad AMR exome AF: 0.0631

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.120

Gnomad SAS exome AF: 0.172

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.101

Gnomad OTH exome AF: 0.0934

GnomAD4 exome AF: 0.109 AC: 125857 AN: 1150598 Hom.: 7322 Cov.: 31 AF XY: 0.111 AC XY: 62779 AN XY: 564174

Gnomad4 AFR exome AF: 0.0956

Gnomad4 AMR exome AF: 0.0628

Gnomad4 ASJ exome AF: 0.0379

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.173

Gnomad4 FIN exome AF: 0.117

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.103 AC: 15663 AN: 152268 Hom.: 861 Cov.: 33 AF XY: 0.104 AC XY: 7729 AN XY: 74462

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.0688

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.120

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.0867

Alfa AF: 0.0960 Hom.: 266

Bravo AF: 0.0944

TwinsUK AF: 0.111 AC: 411

ALSPAC AF: 0.109 AC: 419

ExAC AF: 0.0948 AC: 2206

Asia WGS AF: 0.147 AC: 510 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.8
Dann	Benign	0.52
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.00090	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.025
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.058	T
Polyphen		0.0010	B
Vest4		0.040
MutPred		0.27		Gain of phosphorylation at C1295 (P = 0.0075);
MPC		0.41
ClinPred		0.012	T
GERP RS		1.7
Varity_R		0.044
gMVP		0.082

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: rs1537514; hg19: chr1-11848068; COSMIC: COSV57171901; COSMIC: COSV57171901;