Genetic Variant CELF4:p.Pro406Pro (chr18-37264705-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_020180.4(CELF4):c.1218G>A(p.Pro406Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,579,972 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

CELF4
NM_020180.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.395

Variant links:

Genes affected

CELF4 (HGNC:14015): (CUGBP Elav-like family member 4) Members of the CELF/BRUNOL protein family contain two N-terminal RNA recognition motif (RRM) domains, one C-terminal RRM domain, and a divergent segment of 160-230 aa between the second and third RRM domains. Members of this protein family regulate pre-mRNA alternative splicing and may also be involved in mRNA editing, and translation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CELF4 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 18-37264705-C-T is Benign according to our data. Variant chr18-37264705-C-T is described in ClinVar as [Benign]. Clinvar id is 728639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.395 with no splicing effect.

BS2

High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELF4	NM_020180.4 link	c.1218G>A	p.Pro406Pro	synonymous_variant	Exon 10 of 13	ENST00000420428.7	NP_064565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CELF4	ENST00000420428.7 link	c.1218G>A	p.Pro406Pro	synonymous_variant	Exon 10 of 13	5	NM_020180.4	ENSP00000410584.2	Q9BZC1-1
CELF4	ENST00000603232.6 link	c.1215G>A	p.Pro405Pro	synonymous_variant	Exon 10 of 13	1		ENSP00000474788.2	Q9BZC1-4
CELF4	ENST00000361795.9 link	c.1212G>A	p.Pro404Pro	synonymous_variant	Exon 10 of 13	2		ENSP00000355089.4	Q9BZC1-3

Frequencies

GnomAD3 genomes

AF:

0.000657

AC:

100

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00752

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.000718

AC:

140

AN:

194978

Hom.:

AF XY:

0.000672

AC XY:

AN XY:

104204

show subpopulations

Gnomad AFR exome

AF:

0.000522

Gnomad AMR exome

AF:

0.00109

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00478

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000584

Gnomad NFE exome

AF:

0.000301

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.000447

AC:

638

AN:

1427726

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

297

AN XY:

706630

show subpopulations

Gnomad4 AFR exome

AF:

0.000640

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00911

Gnomad4 SAS exome

AF:

0.0000369

Gnomad4 FIN exome

AF:

0.0000393

Gnomad4 NFE exome

AF:

0.000131

Gnomad4 OTH exome

AF:

0.000982

GnomAD4 genome

AF:

0.000650

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00753

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.000393

Hom.:

Bravo

AF:

0.000729

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CELF4-related disorder

Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over