rs770755917

Positions:

• chr9-108917569-G-A
• chr9-108917569-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003640.5(ELP1):​c.842C>T​(p.Pro281Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,790 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.842C>T	p.Pro281Leu	missense_variant	9/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.500C>T	p.Pro167Leu	missense_variant	9/37		NP_001305289.1
ELP1	XM_047423991.1	c.842C>T	p.Pro281Leu	missense_variant	9/25		XP_047279947.1
ELP1	NM_001330749.2	c.-206C>T		5_prime_UTR_variant	7/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.842C>T	p.Pro281Leu	missense_variant	9/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461790 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial dysautonomia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces proline with leucine at codon 281 of the ELP1 protein (p.Pro281Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs770755917, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.71		Loss of ubiquitination at K284 (P = 0.0982);
MVP		0.69
MPC		0.43
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.69
gMVP		0.43

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: rs770755917; hg19: chr9-111679849;