rs2230791

Variant names:

• chr9-108901474-G-A
• rs2230791
• NM_003640.5:c.1965C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-108901474-G-A
• chr9-108901474-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003640.5(ELP1):​c.1965C>T​(p.Thr655Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 1,611,036 control chromosomes in the GnomAD database, including 5,569 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (846 hom., cov: 31)
  • Exomes 𝑓: 0.075 (4723 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0350
• Publications: 13 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=-0.41).
• BP6: Variant 9-108901474-G-A is Benign according to our data. Variant chr9-108901474-G-A is described in ClinVar as [Benign]. Clinvar id is 137576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.035 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5	c.1965C>T	p.Thr655Thr	synonymous_variant	Exon 18 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1623C>T	p.Thr541Thr	synonymous_variant	Exon 18 of 37		NP_001305289.1
ELP1	NM_001330749.2	c.918C>T	p.Thr306Thr	synonymous_variant	Exon 16 of 35		NP_001317678.1
ELP1	XM_047423991.1	c.1965C>T	p.Thr655Thr	synonymous_variant	Exon 18 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.1965C>T	p.Thr655Thr	synonymous_variant	Exon 18 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.0925 AC: 14064 AN: 152026 Hom.: 847 Cov.: 31

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0620

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.0870

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0789

Gnomad OTH AF: 0.0811

GnomAD2 exomes AF: 0.0695 AC: 17450 AN: 250976 AF XY: 0.0696

Gnomad AFR exome AF: 0.158

Gnomad AMR exome AF: 0.0424

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.0824

Gnomad OTH exome AF: 0.0683

GnomAD4 exome AF: 0.0754 AC: 110033 AN: 1458892 Hom.: 4723 Cov.: 32 AF XY: 0.0746 AC XY: 54162 AN XY: 725936

African (AFR) AF: 0.150 AC: 5015 AN: 33362

American (AMR) AF: 0.0449 AC: 2006 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 754 AN: 26130

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39692

South Asian (SAS) AF: 0.0538 AC: 4637 AN: 86200

European-Finnish (FIN) AF: 0.0804 AC: 4294 AN: 53416

Middle Eastern (MID) AF: 0.0444 AC: 256 AN: 5762

European-Non Finnish (NFE) AF: 0.0801 AC: 88860 AN: 1109300

Other (OTH) AF: 0.0697 AC: 4201 AN: 60312

GnomAD4 genome AF: 0.0925 AC: 14074 AN: 152144 Hom.: 846 Cov.: 31 AF XY: 0.0911 AC XY: 6776 AN XY: 74388

African (AFR) AF: 0.152 AC: 6288 AN: 41456

American (AMR) AF: 0.0618 AC: 945 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3468

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0502 AC: 242 AN: 4820

European-Finnish (FIN) AF: 0.0870 AC: 922 AN: 10596

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0790 AC: 5370 AN: 68010

Other (OTH) AF: 0.0802 AC: 169 AN: 2106

Alfa AF: 0.0897 Hom.: 902

Bravo AF: 0.0946

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.0772

EpiControl AF: 0.0731

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:3

May 10, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Mar 07, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	5.7
DANN	Benign	0.57
PhyloP100		0.035
Mutation Taster		=100/0	polymorphism (auto)

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: rs2230791; hg19: chr9-111663754;