18-37266557-C-T

Variant summary

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

The NM_020180.4(CELF4):c.1141G>A(p.Ala381Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000413 in 1,597,262 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 (★). Synonymous variant affecting the same amino acid position (i.e. A381A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: CELF4 NM_020180.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.62

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21519536).
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELF4	NM_020180.4	c.1141G>A	p.Ala381Thr	missense_variant	9/13	ENST00000420428.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELF4	ENST00000420428.7	c.1141G>A	p.Ala381Thr	missense_variant	9/13	5	NM_020180.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000316 AC: 7 AN: 221174 Hom.: 0 AF XY: 0.0000337 AC XY: 4 AN XY: 118746

Gnomad AFR exome AF: 0.000214

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000374

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000200

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000429 AC: 62 AN: 1445034 Hom.: 0 Cov.: 31 AF XY: 0.0000307 AC XY: 22 AN XY: 716918

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000240

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000483

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000461

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000453

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.1141G>A (p.A381T) alteration is located in exon 9 (coding exon 9) of the CELF4 gene. This alteration results from a G to A substitution at nucleotide position 1141, causing the alanine (A) at amino acid position 381 to be replaced by a threonine (T). 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	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.38
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Benign	0.019
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.56	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.98, 0.0050, 0.0080, 0.032	.;D;B;B;.;B;.;B;.;.;B;.
Vest4		0.24, 0.19, 0.19, 0.20, 0.17, 0.20, 0.23
MVP		0.49
MPC		0.31
ClinPred		0.077	T
GERP RS		4.6
Varity_R		0.18
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs759568975; hg19: chr18-34846520; COSMIC: COSV58470324; COSMIC: COSV58470324;