rs41278359

chr9-108911140-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_003640.5(ELP1):c.1230G>A(p.Pro410=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,614,018 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (53 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -0.192

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-108911140-C-T is Benign according to our data. Variant chr9-108911140-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=4}. Variant chr9-108911140-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.192 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.1230G>A	p.Pro410=	synonymous_variant	12/37	ENST00000374647.10
ELP1	NM_001318360.2	c.888G>A	p.Pro296=	synonymous_variant	12/37
ELP1	NM_001330749.2	c.183G>A	p.Pro61=	synonymous_variant	10/35
ELP1	XM_047423991.1	c.1230G>A	p.Pro410=	synonymous_variant	12/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.1230G>A	p.Pro410=	synonymous_variant	12/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1056 AN: 152042 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00733 AC: 1842 AN: 251410 Hom.: 14 AF XY: 0.00734 AC XY: 997 AN XY: 135882

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.00853

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00739 AC: 10801 AN: 1461858 Hom.: 53 Cov.: 32 AF XY: 0.00722 AC XY: 5254 AN XY: 727228

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00347

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00145

Gnomad4 FIN exome AF: 0.0283

Gnomad4 NFE exome AF: 0.00769

Gnomad4 OTH exome AF: 0.00628

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152160 Hom.: 11 Cov.: 32 AF XY: 0.00809 AC XY: 602 AN XY: 74386

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00517

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0325

Gnomad4 NFE AF: 0.00806

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00623 Hom.: 3

Bravo AF: 0.00517

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00783

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 20, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ELP1: BP4, BP7, BS2 -

Familial dysautonomia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	4.8
Dann	Benign	0.55

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: rs41278359; hg19: chr9-111673420;