ENST00000495759.6:n.*3680G>A

Variant names:

• chr9-108868044-C-T
• rs41305457
• ENST00000495759.6:n.*3680G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000495759.6(ELP1):​n.*3680G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,256 control chromosomes in the GnomAD database, including 1,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1043 hom., cov: 33)
  • Exomes 𝑓: 0.27 (2 hom.)
• Consequence: ELP1 ENST00000495759.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.305
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-108868044-C-T is Benign according to our data. Variant chr9-108868044-C-T is described in ClinVar as [Benign]. Clinvar id is 364545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5	c.*1071G>A		3_prime_UTR_variant	Exon 37 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.*1071G>A		3_prime_UTR_variant	Exon 37 of 37		NP_001305289.1
ELP1	NM_001330749.2	c.*1071G>A		3_prime_UTR_variant	Exon 35 of 35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.*1071G>A		3_prime_UTR_variant	Exon 37 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16446 AN: 152108 Hom.: 1045 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0837

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0447

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.113

GnomAD4 exome AF: 0.267 AC: 8 AN: 30 Hom.: 2 Cov.: 0 AF XY: 0.300 AC XY: 6 AN XY: 20

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.318 AC: 7 AN: 22

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.108 AC: 16454 AN: 152226 Hom.: 1043 Cov.: 33 AF XY: 0.106 AC XY: 7886 AN XY: 74422

African (AFR) AF: 0.104 AC: 4321 AN: 41540

American (AMR) AF: 0.0835 AC: 1276 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5178

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4824

European-Finnish (FIN) AF: 0.140 AC: 1487 AN: 10588

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8309 AN: 68026

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.105 Hom.: 130

Bravo AF: 0.105

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:1

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:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.2
DANN	Benign	0.76
PhyloP100		0.30
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: rs41305457; hg19: chr9-111630324;