9-108929883-G-A

Variant names:

• chr9-108929883-G-A
• rs2230786
• NM_003640.5:c.189C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_003640.5(ELP1):​c.189C>T​(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,842 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L63L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (32 hom., cov: 32)
  • Exomes 𝑓: 0.022 (426 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0500
• Publications: 7 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-108929883-G-A is Benign according to our data. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108929883-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2732/152284) while in subpopulation NFE AF = 0.0246 (1674/68032). AF 95% confidence interval is 0.0236. There are 32 homozygotes in GnomAd4. There are 1339 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 3 of 37	ENST00000374647.10	NP_003631.2
ELP1	XM_047423991.1	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 3 of 25		XP_047279947.1
ELP1	NM_001318360.2	c.-154C>T		5_prime_UTR_variant	Exon 3 of 37		NP_001305289.1
ELP1	NM_001330749.2	c.-671C>T		5_prime_UTR_variant	Exon 3 of 35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.189C>T	p.Leu63Leu	synonymous_variant	Exon 3 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2723 AN: 152166 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00765

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0246

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0182 AC: 4566 AN: 251482 AF XY: 0.0185

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.00650

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0220 AC: 32184 AN: 1461558 Hom.: 426 Cov.: 31 AF XY: 0.0213 AC XY: 15494 AN XY: 727082

African (AFR) AF: 0.0116 AC: 387 AN: 33472

American (AMR) AF: 0.00653 AC: 292 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0123 AC: 321 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.00749 AC: 646 AN: 86236

European-Finnish (FIN) AF: 0.0237 AC: 1268 AN: 53418

Middle Eastern (MID) AF: 0.0108 AC: 60 AN: 5540

European-Non Finnish (NFE) AF: 0.0253 AC: 28099 AN: 1111976

Other (OTH) AF: 0.0183 AC: 1106 AN: 60358

GnomAD4 genome AF: 0.0179 AC: 2732 AN: 152284 Hom.: 32 Cov.: 32 AF XY: 0.0180 AC XY: 1339 AN XY: 74452

African (AFR) AF: 0.0119 AC: 494 AN: 41554

American (AMR) AF: 0.0123 AC: 188 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4830

European-Finnish (FIN) AF: 0.0239 AC: 254 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0246 AC: 1674 AN: 68032

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0185 Hom.: 37

Bravo AF: 0.0167

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0239

EpiControl AF: 0.0202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Apr 03, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial dysautonomia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	5.6
DANN	Benign	0.75
PhyloP100		0.050
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230786; hg19: chr9-111692163;