18-37259211-C-T

Variant names:

• chr18-37259211-C-T
• rs1423529748
• NM_020180.4:c.1303G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_020180.4(CELF4):​c.1303G>A​(p.Ala435Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CELF4 NM_020180.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32893276).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELF4	NM_020180.4	c.1303G>A	p.Ala435Thr	missense_variant	Exon 11 of 13	ENST00000420428.7	NP_064565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELF4	ENST00000420428.7	c.1303G>A	p.Ala435Thr	missense_variant	Exon 11 of 13	5	NM_020180.4	ENSP00000410584.2
CELF4	ENST00000603232.6	c.1300G>A	p.Ala434Thr	missense_variant	Exon 11 of 13	1		ENSP00000474788.2
CELF4	ENST00000361795.9	c.1297G>A	p.Ala433Thr	missense_variant	Exon 11 of 13	2		ENSP00000355089.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461608 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 15, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;.;.;.;T;.;.;.
Eigen	Benign	0.043
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;.;D;D;D
M_CAP	Benign	0.0092	T
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	.;L;.;.;.;L;.;.;.
PrimateAI	Uncertain	0.73	T
REVEL	Benign	0.096
Sift4G	Benign	0.80	T;T;T;T;T;T;.;T;.
Polyphen		0.077	B;B;.;B;.;B;.;P;.
Vest4		0.35
MutPred		0.41		.;Gain of disorder (P = 0.2482);.;.;.;Gain of disorder (P = 0.2482);.;.;.;
MVP		0.45
MPC		2.1
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.22
gMVP		0.32

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: rs1423529748; hg19: chr18-34839174; COSMIC: COSV58463893;