rs886045180

Variant names:

• chr1-11788203-CCTT-C
• rs886045180
• NM_001010881.2:c.3906_3908delTCT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001010881.2(C1orf167):​c.3906_3908delTCT​(p.Leu1303del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,148,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: C1orf167 NM_001010881.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.716
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001010881.2. Strenght limited to Supporting due to length of the change: 1aa.

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.3906_3908delTCT	p.Leu1303del	disruptive_inframe_deletion	Exon 19 of 21	NP_001010881.1
	MTHFR	NM_005957.5	MANE Select	c.*2474_*2476delAAG		3_prime_UTR	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.*2474_*2476delAAG		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.3906_3908delTCT	p.Leu1303del	disruptive_inframe_deletion	Exon 19 of 21	ENSP00000510540.1
	C1orf167	ENST00000444493.5	TSL:1	c.1404_1406delTCT	p.Leu469del	disruptive_inframe_deletion	Exon 8 of 10	ENSP00000398213.1
	MTHFR	ENST00000376590.9	TSL:1 MANE Select	c.*2474_*2476delAAG		3_prime_UTR	Exon 12 of 12	ENSP00000365775.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000348 AC: 4 AN: 1148240 Hom.: 0 AF XY: 0.00000534 AC XY: 3 AN XY: 562028

African (AFR) AF: 0.00 AC: 0 AN: 24344

American (AMR) AF: 0.00 AC: 0 AN: 28190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15918

East Asian (EAS) AF: 0.00 AC: 0 AN: 12712

South Asian (SAS) AF: 0.00 AC: 0 AN: 76098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4380

European-Non Finnish (NFE) AF: 0.00000436 AC: 4 AN: 917926

Other (OTH) AF: 0.00 AC: 0 AN: 41342

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neural tube defects, folate-sensitive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72
Mutation Taster		=93/7	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: rs886045180; hg19: chr1-11848260;