rs368410371

chr9-108918908-G-Achr9-108918908-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_003640.5(ELP1):c.650-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,610,312 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (1 hom.)
• Consequence: ELP1 NM_003640.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002109
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 0.734

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 -10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-108918908-G-A is Benign according to our data. Variant chr9-108918908-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 455972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.650-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374647.10
ELP1	NM_001318360.2	c.308-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ELP1	NM_001330749.2	c.-307-1238C>T		intron_variant
ELP1	XM_047423991.1	c.650-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.650-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000131 AC: 33 AN: 251406 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135882

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000411 AC: 60 AN: 1458144 Hom.: 1 Cov.: 30 AF XY: 0.0000427 AC XY: 31 AN XY: 725674

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74344

Gnomad4 AFR AF: 0.000434

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000988 Hom.: 0

Bravo AF: 0.000215

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 17, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

ELP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.7
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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: rs368410371; hg19: chr9-111681188;