rs2275495

Variant names:

• chr9-108882116-G-A
• rs2275495
• NM_003640.5:c.3285+9C>T

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.3285+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,610,484 control chromosomes in the GnomAD database, including 15,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3203 hom., cov: 32)
  • Exomes 𝑓: 0.12 (12203 hom.)
• Consequence: ELP1 NM_003640.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.47
• 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=-0.84).
• BP6: Variant 9-108882116-G-A is Benign according to our data. Variant chr9-108882116-G-A is described in ClinVar as Benign. ClinVar VariationId is 137582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.323 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.3285+9C>T		intron	N/A	NP_003631.2
	ELP1	NM_001318360.2		c.2943+9C>T		intron	N/A	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.2238+9C>T		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.3285+9C>T		intron	N/A	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.2238+9C>T		intron	N/A	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*1895+9C>T		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27408 AN: 151914 Hom.: 3199 Cov.: 32

Gnomad AFR AF: 0.328

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.161

GnomAD2 exomes AF: 0.143 AC: 35712 AN: 250548 AF XY: 0.133

Gnomad AFR exome AF: 0.337

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.0368

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.120 AC: 175196 AN: 1458452 Hom.: 12203 Cov.: 30 AF XY: 0.118 AC XY: 85356 AN XY: 725754

African (AFR) AF: 0.338 AC: 11272 AN: 33368

American (AMR) AF: 0.241 AC: 10795 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0367 AC: 959 AN: 26122

East Asian (EAS) AF: 0.113 AC: 4494 AN: 39660

South Asian (SAS) AF: 0.0936 AC: 8067 AN: 86180

European-Finnish (FIN) AF: 0.160 AC: 8454 AN: 52938

Middle Eastern (MID) AF: 0.0735 AC: 423 AN: 5758

European-Non Finnish (NFE) AF: 0.111 AC: 123500 AN: 1109412

Other (OTH) AF: 0.120 AC: 7232 AN: 60312

GnomAD4 genome AF: 0.180 AC: 27433 AN: 152032 Hom.: 3203 Cov.: 32 AF XY: 0.181 AC XY: 13455 AN XY: 74334

African (AFR) AF: 0.327 AC: 13566 AN: 41430

American (AMR) AF: 0.184 AC: 2808 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0317 AC: 110 AN: 3472

East Asian (EAS) AF: 0.111 AC: 572 AN: 5176

South Asian (SAS) AF: 0.101 AC: 485 AN: 4812

European-Finnish (FIN) AF: 0.174 AC: 1836 AN: 10556

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7647 AN: 67986

Other (OTH) AF: 0.159 AC: 335 AN: 2112

Alfa AF: 0.148 Hom.: 1427

Bravo AF: 0.193

Asia WGS AF: 0.124 AC: 432 AN: 3478

EpiCase AF: 0.105

EpiControl AF: 0.106

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.49
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs2275495; hg19: chr9-111644396; COSMIC: COSV65896849;