19-18446353-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_006532.4(ELL):c.1660G>A(p.Asp554Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,451,920 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: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ELL NM_006532.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELL	NM_006532.4	c.1660G>A	p.Asp554Asn	missense_variant	10/12	ENST00000262809.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELL	ENST00000262809.9	c.1660G>A	p.Asp554Asn	missense_variant	10/12	1	NM_006532.4	P1
ELL	ENST00000596124.3	c.1261G>A	p.Asp421Asn	missense_variant	10/12	1
ELL	ENST00000594635.6	c.*1495G>A		3_prime_UTR_variant, NMD_transcript_variant	11/13	1
ELL	ENST00000608165.1	n.245G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1451920 Hom.: 0 Cov.: 32 AF XY: 0.00000693 AC XY: 5 AN XY: 721740

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000232

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Jul 05, 2022

The c.1660G>A (p.D554N) 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 1660, causing the aspartic acid (D) at amino acid position 554 to be replaced by an asparagine (N). 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	Uncertain	0.49
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0080	D;.
Sift4G	Benign	0.42	T;T
Polyphen		1.0	D;.
Vest4		0.74
MutPred		0.62		Gain of MoRF binding (P = 0.0519);.;
MVP		0.57
MPC		1.3
ClinPred		0.91	D
GERP RS		4.6
Varity_R		0.46
gMVP		0.56

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: rs1177176329; hg19: chr19-18557163;