NM_013291.3:c.4159G>T

Variant names:

• chr8-144393577-C-A
• rs1554862126
• NM_013291.3:c.4159G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_013291.3(CPSF1):​c.4159G>T​(p.Asp1387Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,604,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CPSF1 NM_013291.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49
• 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 3 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.

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.4159G>T	p.Asp1387Tyr	missense	Exon 37 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.4159G>T	p.Asp1387Tyr	missense	Exon 37 of 38	ENSP00000484669.1	Q10570
	CPSF1	ENST00000620219.4	TSL:1	c.4159G>T	p.Asp1387Tyr	missense	Exon 36 of 37	ENSP00000478145.1	Q10570
	CPSF1	ENST00000886816.1		c.4183G>T	p.Asp1395Tyr	missense	Exon 37 of 38	ENSP00000556875.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000431 AC: 1 AN: 231972 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452548 Hom.: 0 Cov.: 56 AF XY: 0.00 AC XY: 0 AN XY: 721752

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.0000229 AC: 1 AN: 43692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.00 AC: 0 AN: 84368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109826

Other (OTH) AF: 0.00 AC: 0 AN: 60056

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74212

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41364

American (AMR) AF: 0.0000655 AC: 1 AN: 15256

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.40
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Benign	0.71
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Pathogenic	0.81	D
Sift4G	Uncertain	0.027	D
Polyphen		0.14	B
Vest4		0.66
MutPred		0.57		Loss of sheet (P = 0.0181)
MVP		0.59
ClinPred		0.65	D
GERP RS		5.4
Varity_R		0.42
gMVP		0.85
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1554862126; hg19: chr8-145618792;