rs2230793

Variant names:

• chr9-108897203-T-G
• rs2230793
• NM_003640.5:c.2446A>C

Your query was ambiguous. Multiple possible variants found:

• chr9-108897203-T-G
• chr9-108897203-T-A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:7
• Conservation: PhyloP100: 1.83
• Publications: 41 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: Orphanet, G2P
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 137578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.2446A>C	p.Ile816Leu	missense	Exon 23 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.2104A>C	p.Ile702Leu	missense	Exon 23 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.1399A>C	p.Ile467Leu	missense	Exon 21 of 35	NP_001317678.1	F5H2T0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	ENST00000374647.10	TSL:1 MANE Select	c.2446A>C	p.Ile816Leu	missense	Exon 23 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.1399A>C	p.Ile467Leu	missense	Exon 16 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*1056A>C		non_coding_transcript_exon	Exon 17 of 31	ENSP00000433514.2	H0YDF3

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

GnomAD2 exomes AF: 0.224 AC: 56288 AN: 251272 AF XY: 0.215

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 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

African (AFR) AF: 0.449 AC: 15045 AN: 33474

American (AMR) AF: 0.285 AC: 12762 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0843 AC: 2203 AN: 26136

East Asian (EAS) AF: 0.280 AC: 11134 AN: 39694

South Asian (SAS) AF: 0.197 AC: 16952 AN: 86252

European-Finnish (FIN) AF: 0.228 AC: 12182 AN: 53420

Middle Eastern (MID) AF: 0.133 AC: 765 AN: 5768

European-Non Finnish (NFE) AF: 0.187 AC: 208152 AN: 1111754

Other (OTH) AF: 0.200 AC: 12096 AN: 60386

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

African (AFR) AF: 0.438 AC: 18127 AN: 41400

American (AMR) AF: 0.242 AC: 3691 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 261 AN: 3472

East Asian (EAS) AF: 0.272 AC: 1400 AN: 5150

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4810

European-Finnish (FIN) AF: 0.239 AC: 2522 AN: 10564

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12698 AN: 67974

Other (OTH) AF: 0.233 AC: 492 AN: 2114

Alfa AF: 0.212 Hom.: 15241

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial dysautonomia (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.00079	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.33	N
PhyloP100		1.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.073
Sift	Benign	0.36	T
Sift4G	Benign	0.19	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
Mutation Taster		=96/4	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: rs2230793; hg19: chr9-111659483; COSMIC: COSV65896207; COSMIC: COSV65896207;