9-108867856-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003640.5(ELP1):c.*1259C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 152,236 control chromosomes in the GnomAD database, including 669 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.081 (669 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ELP1 NM_003640.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0640

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-108867856-G-C is Benign according to our data. Variant chr9-108867856-G-C is described in ClinVar as [Benign]. Clinvar id is 364539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.*1259C>G		3_prime_UTR_variant	37/37	ENST00000374647.10
ELP1	NM_001318360.2	c.*1259C>G		3_prime_UTR_variant	37/37
ELP1	NM_001330749.2	c.*1259C>G		3_prime_UTR_variant	35/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.*1259C>G		3_prime_UTR_variant	37/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.0809 AC: 12307 AN: 152118 Hom.: 668 Cov.: 33

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0884

Gnomad ASJ AF: 0.0927

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.0790

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0810 AC: 12337 AN: 152236 Hom.: 669 Cov.: 33 AF XY: 0.0845 AC XY: 6292 AN XY: 74442

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.0889

Gnomad4 ASJ AF: 0.0927

Gnomad4 EAS AF: 0.142

Gnomad4 SAS AF: 0.295

Gnomad4 FIN AF: 0.0585

Gnomad4 NFE AF: 0.0781

Gnomad4 OTH AF: 0.0796

Alfa AF: 0.0732 Hom.: 73

Bravo AF: 0.0762

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.55
Dann	Benign	0.66

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: rs13299652; hg19: chr9-111630136;