11-61420021-T-G

Variant names:

• chr11-61420021-T-G
• NM_001142565.3:c.451A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142565.3(CPSF7):​c.451A>C​(p.Asn151His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPSF7 NM_001142565.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48

Genes affected

CPSF7 (HGNC:30098): (cleavage and polyadenylation specific factor 7) Cleavage factor Im (CFIm) is one of six factors necessary for correct cleavage and polyadenylation of pre-mRNAs. CFIm is composed of three different subunits of 25, 59, and 68 kDa, and it functions as a heterotetramer, with a dimer of the 25 kDa subunit binding to two of the 59 or 68 kDa subunits. The protein encoded by this gene represents the 59 kDa subunit, which can interact with the splicing factor U2 snRNP Auxiliary Factor (U2AF) 65 to link the splicing and polyadenylation complexes. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22534713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPSF7	NM_001142565.3	c.451A>C	p.Asn151His	missense_variant	Exon 5 of 10	ENST00000439958.8	NP_001136037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPSF7	ENST00000439958.8	c.451A>C	p.Asn151His	missense_variant	Exon 5 of 10	1	NM_001142565.3	ENSP00000397203.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.580A>C (p.N194H) alteration is located in exon 5 (coding exon 5) of the CPSF7 gene. This alteration results from a A to C substitution at nucleotide position 580, causing the asparagine (N) at amino acid position 194 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.062	.;T;.;.;T;.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.86	D;D;.;D;D;D;D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	.;L;L;L;.;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	4.5	N;N;N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T;T;T;T;T;T
Sift4G	Benign	0.97	T;T;T;T;.;T;.;.
Polyphen		0.020	B;B;B;B;.;.;.;.
Vest4		0.37
MutPred		0.54		.;Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);Loss of ubiquitination at K154 (P = 0.074);
MVP		0.55
MPC		1.9
ClinPred		0.81	D
GERP RS		6.1
Varity_R		0.36
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-61187493;