1-50193868-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2 PP3

The NM_001144774.3(ELAVL4):c.458C>T(p.Ser153Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ELAVL4 NM_001144774.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

ELAVL4 (HGNC:3315): (ELAV like RNA binding protein 4) Enables mRNA 3'-UTR AU-rich region binding activity; poly(A) binding activity; and pre-mRNA intronic pyrimidine-rich binding activity. Involved in 3'-UTR-mediated mRNA stabilization; RNA processing; and positive regulation of 3'-UTR-mediated mRNA stabilization. Predicted to be located in axon; cytoplasm; and dendrite. Predicted to be part of polysomal ribosome. Predicted to be active in glutamatergic synapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ELAVL4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELAVL4	NM_001144774.3	c.458C>T	p.Ser153Leu	missense_variant	4/7	ENST00000371824.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELAVL4	ENST00000371824.7	c.458C>T	p.Ser153Leu	missense_variant	4/7	1	NM_001144774.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727210

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 20, 2023

The c.509C>T (p.S170L) alteration is located in exon 4 (coding exon 4) of the ELAVL4 gene. This alteration results from a C to T substitution at nucleotide position 509, causing the serine (S) at amino acid position 170 to be replaced by a leucine (L). 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	0.18
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.017	D;D;D;D;D;D;D
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D
Polyphen		0.84, 0.94, 0.75, 0.95, 0.87	.;P;.;P;P;P;P
Vest4		0.86
MutPred		0.51		.;.;.;.;.;Loss of disorder (P = 0.0656);Loss of disorder (P = 0.0656);
MVP		0.56
MPC		1.0
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.77
gMVP		0.49

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: rs1175579240; hg19: chr1-50659540; COSMIC: COSV63915417;