chr18-37270783-T-C

Position:

• chr18-37270783-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020180.4(CELF4):​c.1084A>G​(p.Ile362Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,461,646 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: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CELF4 NM_020180.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36095303).
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELF4	NM_020180.4	c.1084A>G	p.Ile362Val	missense_variant	8/13	ENST00000420428.7	NP_064565.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELF4	ENST00000420428.7	c.1084A>G	p.Ile362Val	missense_variant	8/13	5	NM_020180.4	ENSP00000410584.2
CELF4	ENST00000603232.6	c.1081A>G	p.Ile361Val	missense_variant	8/13	1		ENSP00000474788.2
CELF4	ENST00000361795.9	c.1078A>G	p.Ile360Val	missense_variant	8/13	2		ENSP00000355089.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Dec 06, 2024

The c.1084A>G (p.I362V) alteration is located in exon 8 (coding exon 8) of the CELF4 gene. This alteration results from a A to G substitution at nucleotide position 1084, causing the isoleucine (I) at amino acid position 362 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.093	.;.;.;T;.;.;.;T;.;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.82	T;D;D;D;T;T;T;.;T;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.5	.;.;.;L;.;.;.;L;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.48	.;N;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.44	.;T;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.56	T;T;T;T;T;T;T;T;T;.;T;.
Polyphen		0.19, 0.014, 0.010, 0.0060, 0.070	.;B;B;B;.;B;.;B;.;.;B;.
Vest4		0.61, 0.60, 0.57, 0.56, 0.61, 0.59, 0.58, 0.54
MVP		0.55
MPC		0.31
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.14
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372922900; hg19: chr18-34850746;