chr1-11788011-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001010881.2(C1orf167):​c.3812G>A​(p.Cys1271Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000869 in 1,150,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: not found (cov: 33)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: C1orf167 NM_001010881.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.393
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05962971).

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>A	p.Cys1271Tyr	missense	Exon 18 of 21	NP_001010881.1
	MTHFR	NM_005957.5	MANE Select	c.*2669C>T		3_prime_UTR	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.*2669C>T		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>A	p.Cys1271Tyr	missense	Exon 18 of 21	ENSP00000510540.1
	C1orf167	ENST00000444493.5	TSL:1	c.1310G>A	p.Cys437Tyr	missense	Exon 7 of 10	ENSP00000398213.1
	C1orf167	ENST00000449278.1	TSL:1	c.1139G>A	p.Cys380Tyr	missense	Exon 6 of 9	ENSP00000399272.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.69e-7 AC: 1 AN: 1150678 Hom.: 0 Cov.: 31 AF XY: 0.00000177 AC XY: 1 AN XY: 564220

African (AFR) AF: 0.00 AC: 0 AN: 24348

American (AMR) AF: 0.00 AC: 0 AN: 28038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15854

East Asian (EAS) AF: 0.00 AC: 0 AN: 12828

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 76040

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4398

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920296

Other (OTH) AF: 0.00 AC: 0 AN: 41544

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.0
DANN	Benign	0.57
DEOGEN2	Benign	0.029	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.39
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.042	D
Polyphen		0.0010	B
Vest4		0.11
MutPred		0.29		Loss of methylation at K1296 (P = 0.0148)
MVP		0.048
MPC		0.57
ClinPred		0.060	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.10
Mutation Taster		=99/1	polymorphism

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;