9-108919260-TG-TGG

Position:

• chr9-108919260-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003640.5(ELP1):​c.641dupC​(p.Glu215fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELP1 NM_003640.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.54

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.641dupC	p.Glu215fs	frameshift_variant	7/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.299dupC	p.Glu101fs	frameshift_variant	7/37		NP_001305289.1
ELP1	XM_047423991.1	c.641dupC	p.Glu215fs	frameshift_variant	7/25		XP_047279947.1
ELP1	NM_001330749.2	c.-307-1591dupC		intron_variant			NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.641dupC	p.Glu215fs	frameshift_variant	7/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: rs759412460; hg19: chr9-111681540;