18-37270855-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_020180.4(CELF4):c.1012G>A(p.Val338Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,613,668 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (4 hom.)
• Consequence: CELF4 NM_020180.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03110385).
• BP6: Variant 18-37270855-C-T is Benign according to our data. Variant chr18-37270855-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 219 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELF4	NM_020180.4	c.1012G>A	p.Val338Met	missense_variant	8/13	ENST00000420428.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELF4	ENST00000420428.7	c.1012G>A	p.Val338Met	missense_variant	8/13	5	NM_020180.4	P4

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00154 AC: 385 AN: 250564 Hom.: 1 AF XY: 0.00158 AC XY: 214 AN XY: 135464

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00280 AC: 4098 AN: 1461334 Hom.: 4 Cov.: 31 AF XY: 0.00274 AC XY: 1991 AN XY: 726938

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.000575

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000151

Gnomad4 NFE exome AF: 0.00337

Gnomad4 OTH exome AF: 0.00238

GnomAD4 genome AF: 0.00144 AC: 219 AN: 152334 Hom.: 1 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74488

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000914

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00159

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00136 AC: 165

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CELF4-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2021

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
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.0039	N
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.031	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Benign	0.067	T;T;D;D;D;D;T;D;T;.;D;.
Polyphen		0.75, 0.59, 0.94, 0.74, 1.0	.;P;P;P;.;P;.;P;.;.;D;.
Vest4		0.75, 0.81, 0.84, 0.81, 0.79, 0.84, 0.78
MVP		0.73
MPC		0.78
ClinPred		0.048	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.43

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: rs146847221; hg19: chr18-34850818; COSMIC: COSV104642872; COSMIC: COSV104642872;