1-11788011-G-C

Variant names:

• chr1-11788011-G-C
• rs1537514
• NM_001010881.2:c.3812G>C

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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
• Publications: 52 publications found

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]

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010881.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf167	NM_001010881.2	MANE Select	c.3812G>C	p.Cys1271Ser	missense	Exon 18 of 21	NP_001010881.1
	MTHFR	NM_005957.5	MANE Select	c.*2669C>G		3_prime_UTR	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.*2669C>G		3_prime_UTR	Exon 12 of 12	NP_001317287.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf167	ENST00000688073.1	MANE Select	c.3812G>C	p.Cys1271Ser	missense	Exon 18 of 21	ENSP00000510540.1
	C1orf167	ENST00000444493.5	TSL:1	c.1310G>C	p.Cys437Ser	missense	Exon 7 of 10	ENSP00000398213.1
	C1orf167	ENST00000449278.1	TSL:1	c.1139G>C	p.Cys380Ser	missense	Exon 6 of 9	ENSP00000399272.1

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

GnomAD2 exomes AF: 0.105 AC: 15680 AN: 149868 AF XY: 0.109

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 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

African (AFR) AF: 0.0956 AC: 2328 AN: 24344

American (AMR) AF: 0.0628 AC: 1759 AN: 28028

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 601 AN: 15852

East Asian (EAS) AF: 0.119 AC: 1530 AN: 12828

South Asian (SAS) AF: 0.173 AC: 13140 AN: 76018

European-Finnish (FIN) AF: 0.117 AC: 3199 AN: 27330

Middle Eastern (MID) AF: 0.0473 AC: 208 AN: 4398

European-Non Finnish (NFE) AF: 0.107 AC: 98475 AN: 920260

Other (OTH) AF: 0.111 AC: 4617 AN: 41540

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

African (AFR) AF: 0.101 AC: 4213 AN: 41560

American (AMR) AF: 0.0688 AC: 1052 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0366 AC: 127 AN: 3472

East Asian (EAS) AF: 0.120 AC: 621 AN: 5178

South Asian (SAS) AF: 0.192 AC: 928 AN: 4824

European-Finnish (FIN) AF: 0.128 AC: 1362 AN: 10604

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7113 AN: 68018

Other (OTH) AF: 0.0867 AC: 183 AN: 2110

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 v4.9

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
PhyloP100		-0.39
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
Mutation Taster		=99/1	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: rs1537514; hg19: chr1-11848068; COSMIC: COSV57171901; COSMIC: COSV57171901;