19-18446350-C-T

Variant summary

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

The NM_006532.4(ELL):c.1663G>A(p.Ala555Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ELL NM_006532.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

ELL (HGNC:23114): (elongation factor for RNA polymerase II) Enables phosphatase binding activity. Involved in positive regulation of transcription, DNA-templated and snRNA transcription. Located in cytosol; nuclear body; and transcriptionally active chromatin. 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=0.16118127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELL	NM_006532.4	c.1663G>A	p.Ala555Thr	missense_variant	10/12	ENST00000262809.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELL	ENST00000262809.9	c.1663G>A	p.Ala555Thr	missense_variant	10/12	1	NM_006532.4	P1
ELL	ENST00000596124.3	c.1264G>A	p.Ala422Thr	missense_variant	10/12	1
ELL	ENST00000594635.6	c.*1498G>A		3_prime_UTR_variant, NMD_transcript_variant	11/13	1
ELL	ENST00000608165.1	n.248G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450372 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 720852

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000825 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

Sep 14, 2022

The c.1663G>A (p.A555T) alteration is located in exon 10 (coding exon 10) of the ELL gene. This alteration results from a G to A substitution at nucleotide position 1663, causing the alanine (A) at amino acid position 555 to be replaced by a threonine (T). 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	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.51	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.040
Sift	Benign	0.28	T;.
Sift4G	Benign	0.17	T;T
Polyphen		0.53	P;.
Vest4		0.33
MutPred		0.48		Gain of phosphorylation at T551 (P = 0.0891);.;
MVP		0.36
MPC		0.70
ClinPred		0.25	T
GERP RS		4.6
Varity_R		0.099
gMVP		0.062

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: rs778608559; hg19: chr19-18557160;