15-43776868-G-C

Position:

• chr15-43776868-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025165.3(ELL3):​c.34C>G​(p.Leu12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ELL3 NM_025165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

ELL3 (HGNC:23113): (elongation factor for RNA polymerase II 3) Predicted to enable cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of transcription, DNA-templated and transcription by RNA polymerase II. Located in several cellular components, including chromosome; cytosol; and nuclear lumen. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21433526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELL3	NM_025165.3	c.34C>G	p.Leu12Val	missense_variant	1/11	ENST00000319359.8	NP_079441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELL3	ENST00000319359.8	c.34C>G	p.Leu12Val	missense_variant	1/11	1	NM_025165.3	ENSP00000320346	P1
ELL3	ENST00000433927.1	c.124C>G	p.Leu42Val	missense_variant	2/6	5		ENSP00000404209
ELL3	ENST00000486851.5	n.99C>G		non_coding_transcript_exon_variant	1/5	2
ELL3	ENST00000497700.1	n.101C>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Nov 29, 2023

The c.34C>G (p.L12V) alteration is located in exon 1 (coding exon 1) of the ELL3 gene. This alteration results from a C to G substitution at nucleotide position 34, causing the leucine (L) at amino acid position 12 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	0.10
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0038	T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.063
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.025	D;.
Polyphen		0.024	B;.
Vest4		0.15
MutPred		0.75		Gain of sheet (P = 0.0477);.;
MVP		0.37
MPC		0.26
ClinPred		0.35	T
GERP RS		2.3
Varity_R		0.070
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1273706443; hg19: chr15-44069066;