9-108868044-C-T

Position:

• chr9-108868044-C-T

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.*1071G>A variant causes a 3 prime UTR 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 NM_003640.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.305

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 (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/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.*1071G>A		3_prime_UTR_variant	37/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.*1071G>A		3_prime_UTR_variant	37/37		NP_001305289.1
ELP1	NM_001330749.2	c.*1071G>A		3_prime_UTR_variant	35/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.*1071G>A		3_prime_UTR_variant	37/37	1	NM_003640.5	ENSP00000363779	P1

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

Gnomad4 FIN exome AF: 0.318

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0835

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0452

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.112

Alfa AF: 0.105 Hom.: 128

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.2
DANN	Benign	0.76

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: rs41305457; hg19: chr9-111630324;