5-173889849-C-A

Variant names:

• chr5-173889849-C-A
• rs774985810
• NM_030627.4:c.116C>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_030627.4(CPEB4):​c.116C>A​(p.Pro39His) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CPEB4 NM_030627.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

CPEB4 (HGNC:21747): (cytoplasmic polyadenylation element binding protein 4) Enables RNA binding activity. Predicted to be involved in several processes, including cellular response to glucose starvation; negative regulation of cytoplasmic translation; and response to ischemia. Located in cytoplasm and nucleus. Biomarker of liver cirrhosis; portal hypertension; and primary biliary cholangitis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18979013).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPEB4	NM_030627.4	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 10	ENST00000265085.10	NP_085130.2
CPEB4	NM_001308189.2	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 9		NP_001295118.1
CPEB4	NM_001308191.2	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 8		NP_001295120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPEB4	ENST00000265085.10	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 10	1	NM_030627.4	ENSP00000265085.5
CPEB4	ENST00000334035.9	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 9	1		ENSP00000334533.5
CPEB4	ENST00000520867.5	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 8	1		ENSP00000429092.1
CPEB4	ENST00000519835.5	c.116C>A	p.Pro39His	missense_variant	Exon 1 of 7	1		ENSP00000429048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251226 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS 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: 0.00000410 AC: 6 AN: 1461894 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.116C>A (p.P39H) alteration is located in exon 1 (coding exon 1) of the CPEB4 gene. This alteration results from a C to A substitution at nucleotide position 116, causing the proline (P) at amino acid position 39 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	0.097
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.99	N;N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.41	T;T;T;T
Polyphen		0.74	P;P;P;P
Vest4		0.33
MutPred		0.15		Loss of glycosylation at P39 (P = 0.0385);Loss of glycosylation at P39 (P = 0.0385);Loss of glycosylation at P39 (P = 0.0385);Loss of glycosylation at P39 (P = 0.0385);
MVP		0.26
MPC		1.1
ClinPred		0.56	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs774985810; hg19: chr5-173316852;