15-43776783-C-A

Variant names:

• chr15-43776783-C-A
• rs150779428
• NM_025165.3:c.119G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_025165.3(ELL3):​c.119G>T​(p.Cys40Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,605,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C40G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ELL3 NM_025165.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.811

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]

ENSG00000262560 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.063574046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELL3	NM_025165.3	c.119G>T	p.Cys40Phe	missense_variant	Exon 1 of 11	ENST00000319359.8	NP_079441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELL3	ENST00000319359.8	c.119G>T	p.Cys40Phe	missense_variant	Exon 1 of 11	1	NM_025165.3	ENSP00000320346.3
ENSG00000262560	ENST00000417761.2	n.*440-239G>T		intron_variant	Intron 7 of 16	2		ENSP00000415219.2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152288 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000177 AC: 43 AN: 243278 AF XY: 0.000220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000156

Gnomad OTH exome AF: 0.000677

GnomAD4 exome AF: 0.000147 AC: 213 AN: 1453458 Hom.: 0 Cov.: 33 AF XY: 0.000151 AC XY: 109 AN XY: 721554

Gnomad4 AFR exome AF: 0.0000902 AC: 3 AN: 33256

Gnomad4 AMR exome AF: 0.000249 AC: 11 AN: 44164

Gnomad4 ASJ exome AF: 0.00170 AC: 44 AN: 25830

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39456

Gnomad4 SAS exome AF: 0.0000584 AC: 5 AN: 85650

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 52968

Gnomad4 NFE exome AF: 0.000111 AC: 123 AN: 1106556

Gnomad4 Remaining exome AF: 0.000284 AC: 17 AN: 59850

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152406 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74532

Gnomad4 AFR AF: 0.0000481 AC: 0.0000480723 AN: 0.0000480723

Gnomad4 AMR AF: 0.000326 AC: 0.000326499 AN: 0.000326499

Gnomad4 ASJ AF: 0.000864 AC: 0.000864055 AN: 0.000864055

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000147 AC: 0.000146972 AN: 0.000146972

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000174

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>T (p.C40F) alteration is located in exon 1 (coding exon 1) of the ELL3 gene. This alteration results from a G to T substitution at nucleotide position 119, causing the cysteine (C) at amino acid position 40 to be replaced by a phenylalanine (F). 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	0.27
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0028	T;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.18
Sift	Benign	0.62	T;T
Sift4G	Uncertain	0.0080	D;.
Polyphen		1.0	D;.
Vest4		0.46
MVP		0.69
MPC		0.89
ClinPred		0.10	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.32
Mutation Taster		=86/14	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

Publications

LitVar

Other links and lift over

dbSNP: rs150779428; hg19: chr15-44068981;