9-108897203-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003640.5(ELP1):c.2446A>C(p.Ile816Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,613,558 control chromosomes in the GnomAD database, including 37,443 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6431 hom., cov: 32)
  • Exomes 𝑓: 0.20 (31012 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.83

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.942915E-4).
• BP6: Variant 9-108897203-T-G is Benign according to our data. Variant chr9-108897203-T-G is described in ClinVar as [Benign]. Clinvar id is 137578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108897203-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.2446A>C	p.Ile816Leu	missense_variant	23/37	ENST00000374647.10
ELP1	NM_001318360.2	c.2104A>C	p.Ile702Leu	missense_variant	23/37
ELP1	NM_001330749.2	c.1399A>C	p.Ile467Leu	missense_variant	21/35
ELP1	XM_047423991.1	c.2446A>C	p.Ile816Leu	missense_variant	23/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.2446A>C	p.Ile816Leu	missense_variant	23/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40468 AN: 151832 Hom.: 6420 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.0752

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.235

GnomAD3 exomes AF: 0.224 AC: 56288 AN: 251272 Hom.: 7069 AF XY: 0.215 AC XY: 29228 AN XY: 135794

Gnomad AFR exome AF: 0.450

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.0841

Gnomad EAS exome AF: 0.269

Gnomad SAS exome AF: 0.199

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.184

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.199 AC: 291291 AN: 1461608 Hom.: 31012 Cov.: 35 AF XY: 0.198 AC XY: 143630 AN XY: 727118

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.285

Gnomad4 ASJ exome AF: 0.0843

Gnomad4 EAS exome AF: 0.280

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.267 AC: 40515 AN: 151950 Hom.: 6431 Cov.: 32 AF XY: 0.267 AC XY: 19822 AN XY: 74284

Gnomad4 AFR AF: 0.438

Gnomad4 AMR AF: 0.242

Gnomad4 ASJ AF: 0.0752

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.233

Alfa AF: 0.198 Hom.: 8651

Bravo AF: 0.280

TwinsUK AF: 0.190 AC: 705

ALSPAC AF: 0.198 AC: 765

ESP6500AA AF: 0.441 AC: 1945

ESP6500EA AF: 0.183 AC: 1575

ExAC AF: 0.227 AC: 27570

Asia WGS AF: 0.266 AC: 923 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.174

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.93
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.00079	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.33	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.073
Sift	Benign	0.36	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.0	B;.
Vest4		0.11
MutPred		0.35		Loss of methylation at K815 (P = 0.0878);.;
MPC		0.071
ClinPred		0.0040	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.46

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: rs2230793; hg19: chr9-111659483; COSMIC: COSV65896207; COSMIC: COSV65896207;