chr18-37253912-T-A

Variant names:

• chr18-37253912-T-A
• rs2067198042
• NM_020180.4:c.1360A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_020180.4(CELF4):​c.1360A>T​(p.Ser454Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000416 in 1,441,364 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S454G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: CELF4 NM_020180.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020180.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELF4	NM_020180.4	MANE Select	c.1360A>T	p.Ser454Cys	missense	Exon 12 of 13	NP_064565.1	Q9BZC1-1
	CELF4	NM_001353740.2		c.1439A>T	p.Gln480Leu	missense	Exon 13 of 15	NP_001340669.1
	CELF4	NM_001353749.2		c.1436A>T	p.Gln479Leu	missense	Exon 13 of 15	NP_001340678.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CELF4	ENST00000420428.7	TSL:5 MANE Select	c.1360A>T	p.Ser454Cys	missense	Exon 12 of 13	ENSP00000410584.2	Q9BZC1-1
	CELF4	ENST00000591282.5	TSL:1	c.1360A>T	p.Ser454Cys	missense	Exon 12 of 12	ENSP00000464794.1	Q9BZC1-1
	CELF4	ENST00000603232.6	TSL:1	c.1357A>T	p.Ser453Cys	missense	Exon 12 of 13	ENSP00000474788.2	Q9BZC1-4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1441364 Hom.: 0 Cov.: 32 AF XY: 0.00000279 AC XY: 2 AN XY: 717574

African (AFR) AF: 0.00 AC: 0 AN: 32174

American (AMR) AF: 0.00 AC: 0 AN: 43958

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25280

East Asian (EAS) AF: 0.00 AC: 0 AN: 37928

South Asian (SAS) AF: 0.00 AC: 0 AN: 85086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4990

European-Non Finnish (NFE) AF: 0.00000545 AC: 6 AN: 1100678

Other (OTH) AF: 0.00 AC: 0 AN: 59080

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.26
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.035	D
Polyphen		0.95	P
Vest4		0.75
MutPred		0.46		Loss of disorder (P = 0.0137)
MVP		0.66
MPC		1.7
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.46
gMVP		0.77
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2067198042; hg19: chr18-34833875;