chr1-11789386-C-T

Variant names:

• chr1-11789386-C-T
• rs375481053
• ENST00000449278.1:c.1523C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000449278.1(C1orf167):​c.1523C>T​(p.Pro508Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000792 in 1,303,442 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/6 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 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (3 hom.)
• Consequence: C1orf167 ENST00000449278.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.11
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.005).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000449278.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf167	NM_001010881.2	MANE Select	c.4290C>T	p.Ala1430Ala	synonymous	Exon 21 of 21	NP_001010881.1
	MTHFR	NM_005957.5	MANE Select	c.*1294G>A		3_prime_UTR	Exon 12 of 12	NP_005948.3
	MTHFR	NM_001330358.2		c.*1294G>A		3_prime_UTR	Exon 12 of 12	NP_001317287.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1orf167	ENST00000449278.1	TSL:1	c.1523C>T	p.Pro508Leu	missense	Exon 9 of 9	ENSP00000399272.1
	C1orf167	ENST00000688073.1	MANE Select	c.4290C>T	p.Ala1430Ala	synonymous	Exon 21 of 21	ENSP00000510540.1
	C1orf167	ENST00000444493.5	TSL:1	c.1788C>T	p.Ala596Ala	synonymous	Exon 10 of 10	ENSP00000398213.1

Frequencies

GnomAD3 genomes AF: 0.000514 AC: 78 AN: 151604 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000707

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.000562 AC: 84 AN: 149546 AF XY: 0.000534

Gnomad AFR exome AF: 0.000444

Gnomad AMR exome AF: 0.000692

Gnomad ASJ exome AF: 0.000955

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000450

Gnomad NFE exome AF: 0.000776

Gnomad OTH exome AF: 0.000932

GnomAD4 exome AF: 0.000828 AC: 954 AN: 1151838 Hom.: 3 Cov.: 29 AF XY: 0.000765 AC XY: 432 AN XY: 564810

African (AFR) AF: 0.000328 AC: 8 AN: 24414

American (AMR) AF: 0.000602 AC: 17 AN: 28262

Ashkenazi Jewish (ASJ) AF: 0.000816 AC: 13 AN: 15934

East Asian (EAS) AF: 0.00 AC: 0 AN: 12844

South Asian (SAS) AF: 0.0000394 AC: 3 AN: 76194

European-Finnish (FIN) AF: 0.000329 AC: 9 AN: 27338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4324

European-Non Finnish (NFE) AF: 0.000959 AC: 883 AN: 920920

Other (OTH) AF: 0.000505 AC: 21 AN: 41608

GnomAD4 genome AF: 0.000514 AC: 78 AN: 151604 Hom.: 0 Cov.: 33 AF XY: 0.000621 AC XY: 46 AN XY: 74044

African (AFR) AF: 0.000170 AC: 7 AN: 41226

American (AMR) AF: 0.000919 AC: 14 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.000379 AC: 4 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000707 AC: 48 AN: 67886

Other (OTH) AF: 0.000483 AC: 1 AN: 2072

Alfa AF: 0.000701 Hom.: 0

Bravo AF: 0.000642

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.35
DANN	Benign	0.90
PhyloP100		-3.1
Mutation Taster		=100/0	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: rs375481053; hg19: chr1-11849443;