chr9-108899816-A-G

Variant names:

• chr9-108899816-A-G
• rs111033171
• NM_003640.5:c.2204+6T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PS3 PP5_Very_Strong BP4

The NM_003640.5(ELP1):​c.2204+6T>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000394 in 1,611,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000698209: multiple splicing studies have shown that this variant causes skipping of exon 20 (Slaugenhaupt_2001" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: ELP1 NM_003640.5 splice_region, intron
• Scores: Splicing: ADA: 0.6565
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 U:1 O:2
• Conservation: PhyloP100: 4.01
• Publications: 32 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: Orphanet, G2P
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000698209: multiple splicing studies have shown that this variant causes skipping of exon 20 (Slaugenhaupt_2001; Anderson_2001).; SCV000712784: This variant was demonstrated to lead to aberrant splicing in vitro (Ibrahim 2007).; SCV000916278: The c.2204+6T>C variant has been shown to affect mRNA splicing and cause tissue-specific skipping of exon 20, which leads to changes in neuronal gene expression and development (Slaugenhaupt et al. 2001; Anderson et al. 2001; Boone et al. 2012).; SCV001142401: Splicing study demenstrated that normal splicing of the IKAP transcript results in removal of introns 19 and 20 and in retention of exon 20. In comparison, c.2204+6T>C in the donor splice site of intron 20 in the mutant allele results in removal of introns 19 and 20 and exon 20 (PMID: 11179021).; SCV000218960: Experimental studies have shown that this variant affects ELP1 function (PMID: 11179008, 11179021, 22190446, 23515154).; SCV000589336: Functional studies in a mouse model show that c.2204+6 T>C causes alternative splicing in specific tissues and results in the skipping of exon 20 in the brain and other neuronal tissue (Bochner et al., 2013); SCV002754700: Skipping of exon 20, which is predicted to result in a frameshift, was detected in brain tissue from an individual affected with FD as well as in fibroblasts derived from multiple FD patients (Slaugenhaupt, 2001; Boone, 2012; Bruun, 2018; Ibrahim, 2007).
• PP5: Variant 9-108899816-A-G is Pathogenic according to our data. Variant chr9-108899816-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 6085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.2204+6T>C		splice_region intron	N/A	NP_003631.2
	ELP1	NM_001318360.2		c.1862+6T>C		splice_region intron	N/A	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.1157+6T>C		splice_region intron	N/A	NP_001317678.1	F5H2T0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	ENST00000374647.10	TSL:1 MANE Select	c.2204+6T>C		splice_region intron	N/A	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.1157+6T>C		splice_region intron	N/A	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*814+6T>C		splice_region intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000649 AC: 163 AN: 251240 AF XY: 0.000626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000382 AC: 558 AN: 1459050 Hom.: 0 Cov.: 30 AF XY: 0.000408 AC XY: 296 AN XY: 726186

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 399 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000739 AC: 82 AN: 1109444

Other (OTH) AF: 0.00124 AC: 75 AN: 60302

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74372

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.000442

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	Familial dysautonomia (12)
5	-	-	not provided (6)
-	1	-	Charcot-Marie-Tooth disease (1)
1	-	-	Familial dysautonomia;C0025149:Medulloblastoma (1)
1	-	-	Medulloblastoma (1)
1	-	-	not specified (1)
1	-	-	Primary dysautonomia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.90
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.66
dbscSNV1_RF	Pathogenic	0.85
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

Other links and lift over

dbSNP: rs111033171; hg19: chr9-111662096;