8-144393705-C-T

Variant names:

• chr8-144393705-C-T
• rs1253104285
• NM_013291.3:c.4107G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_013291.3(CPSF1):​c.4107G>A​(p.Met1369Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000128 in 1,566,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CPSF1 NM_013291.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.22
• Publications: 0 publications found

Genes affected

CPSF1 (HGNC:2324): (cleavage and polyadenylation specific factor 1) Cleavage and polyadenylation specificity factor (CPSF) is a multisubunit complex that plays a central role in 3-prime processing of pre-mRNAs. CPSF recognizes the AAUAAA signal in the pre-mRNA and interacts with other proteins to facilitate both RNA cleavage and poly(A) synthesis. CPSF1 is the largest subunit of the CPSF complex (Murthy and Manley, 1995 [PubMed 7590244]).[supplied by OMIM, Mar 2008]

CPSF1 Gene-Disease associations (from GenCC):

• myopia 27

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Trascript score misZ: 2.0251 (below the threshold of 3.09). GenCC associations: The gene is linked to myopia 27.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3408808).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013291.3. 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
	CPSF1	NM_013291.3	MANE Select	c.4107G>A	p.Met1369Ile	missense	Exon 36 of 38	NP_037423.2	Q10570

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPSF1	ENST00000616140.2	TSL:1 MANE Select	c.4107G>A	p.Met1369Ile	missense	Exon 36 of 38	ENSP00000484669.1	Q10570
	CPSF1	ENST00000620219.4	TSL:1	c.4107G>A	p.Met1369Ile	missense	Exon 35 of 37	ENSP00000478145.1	Q10570
	CPSF1	ENST00000886816.1		c.4131G>A	p.Met1377Ile	missense	Exon 36 of 38	ENSP00000556875.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152088 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000555 AC: 1 AN: 180134 AF XY: 0.0000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1413994 Hom.: 0 Cov.: 56 AF XY: 0.00 AC XY: 0 AN XY: 700608

African (AFR) AF: 0.00 AC: 0 AN: 33038

American (AMR) AF: 0.00 AC: 0 AN: 37894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25430

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 38006

South Asian (SAS) AF: 0.00 AC: 0 AN: 81746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094736

Other (OTH) AF: 0.00 AC: 0 AN: 58962

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41514

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Benign	0.82
DEOGEN2	Benign	0.058	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.029
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.2
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.48	T
Polyphen		0.080	B
Vest4		0.58
MutPred		0.49		Loss of disorder (P = 0.0969)
MVP		0.40
ClinPred		0.20	T
GERP RS		5.4
Varity_R		0.84
gMVP		0.76
Mutation Taster		=70/30	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: rs1253104285; hg19: chr8-145618920; COSMIC: COSV58234519; COSMIC: COSV58234519;