rs4369056

Variant names:

• chr9-108906158-C-T
• rs4369056
• NM_003640.5:c.1643+145G>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.1643+145G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 764,234 control chromosomes in the GnomAD database, including 11,443 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3466 hom., cov: 32)
  • Exomes 𝑓: 0.15 (7977 hom.)
• Consequence: ELP1 NM_003640.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.702
• Publications: 11 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 (BayesDel_noAF=-0.89).
• BP6: Variant 9-108906158-C-T is Benign according to our data. Variant chr9-108906158-C-T is described in ClinVar as Benign. ClinVar VariationId is 1229125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.31 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.1643+145G>A		intron	N/A	NP_003631.2
	ELP1	NM_001318360.2		c.1301+145G>A		intron	N/A	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.596+145G>A		intron	N/A	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.1643+145G>A		intron	N/A	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.596+145G>A		intron	N/A	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*253+145G>A		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29583 AN: 151956 Hom.: 3456 Cov.: 32

Gnomad AFR AF: 0.314

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0626

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.165

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.150 AC: 91775 AN: 612158 Hom.: 7977 AF XY: 0.149 AC XY: 48188 AN XY: 324410

African (AFR) AF: 0.316 AC: 5184 AN: 16388

American (AMR) AF: 0.234 AC: 7087 AN: 30316

Ashkenazi Jewish (ASJ) AF: 0.0696 AC: 1269 AN: 18226

East Asian (EAS) AF: 0.288 AC: 9436 AN: 32750

South Asian (SAS) AF: 0.173 AC: 9931 AN: 57364

European-Finnish (FIN) AF: 0.160 AC: 6122 AN: 38232

Middle Eastern (MID) AF: 0.103 AC: 270 AN: 2632

European-Non Finnish (NFE) AF: 0.124 AC: 47707 AN: 384316

Other (OTH) AF: 0.149 AC: 4769 AN: 31934

GnomAD4 genome AF: 0.195 AC: 29629 AN: 152076 Hom.: 3466 Cov.: 32 AF XY: 0.197 AC XY: 14633 AN XY: 74318

African (AFR) AF: 0.315 AC: 13049 AN: 41448

American (AMR) AF: 0.193 AC: 2952 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0626 AC: 217 AN: 3466

East Asian (EAS) AF: 0.285 AC: 1473 AN: 5174

South Asian (SAS) AF: 0.201 AC: 969 AN: 4822

European-Finnish (FIN) AF: 0.165 AC: 1750 AN: 10578

Middle Eastern (MID) AF: 0.120 AC: 35 AN: 292

European-Non Finnish (NFE) AF: 0.126 AC: 8566 AN: 67994

Other (OTH) AF: 0.170 AC: 360 AN: 2112

Alfa AF: 0.144 Hom.: 985

Bravo AF: 0.207

Asia WGS AF: 0.255 AC: 888 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.0
DANN	Benign	0.52
PhyloP100		-0.70
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4369056;

hg19: chr9-111668438;

COSMIC: COSV65898078;