NM_003640.5:c.2803A>G

Variant names:

• chr9-108894000-T-C
• rs145484092
• NM_003640.5:c.2803A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003640.5(ELP1):​c.2803A>G​(p.Thr935Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000138 in 1,453,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T935S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.04
• Publications: 1 publications found

Genes affected

ELP1 (HGNC:5959): (elongator acetyltransferase complex subunit 1) The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ELP1 Gene-Disease associations (from GenCC):

• primary dysautonomia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Riley-Day syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.2803A>G	p.Thr935Ala	missense	Exon 26 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.2461A>G	p.Thr821Ala	missense	Exon 26 of 37	NP_001305289.1
	ELP1	NM_001330749.2		c.1756A>G	p.Thr586Ala	missense	Exon 24 of 35	NP_001317678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	ENST00000374647.10	TSL:1 MANE Select	c.2803A>G	p.Thr935Ala	missense	Exon 26 of 37	ENSP00000363779.5
	ELP1	ENST00000537196.1	TSL:1	c.1756A>G	p.Thr586Ala	missense	Exon 19 of 30	ENSP00000439367.1
	ELP1	ENST00000495759.6	TSL:1	n.*1413A>G		non_coding_transcript_exon	Exon 20 of 31	ENSP00000433514.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251036 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1453062 Hom.: 0 Cov.: 28 AF XY: 0.00000829 AC XY: 6 AN XY: 723528

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.0000224 AC: 1 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.0000172 AC: 19 AN: 1104114

Other (OTH) AF: 0.00 AC: 0 AN: 60142

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 935 of the ELP1 protein (p.Thr935Ala). This variant is present in population databases (rs145484092, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1390233). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ELP1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	0.0028	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0089	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.036	D
Polyphen		0.54	P
Vest4		0.52
MutPred		0.52		Loss of phosphorylation at T935 (P = 0.028)
MVP		0.52
MPC		0.30
ClinPred		0.72	D
GERP RS		5.9
Varity_R		0.36
gMVP		0.24
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs145484092; hg19: chr9-111656280;