rs41278359

Variant names:

• chr9-108911140-C-T
• rs41278359
• NM_003640.5:c.1230G>A
• ELP1 p.Pro410Pro

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_003640.5(ELP1):​c.1230G>A​(p.Pro410Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,614,018 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0074 (53 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: -0.192
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-108911140-C-T is Benign according to our data. Variant chr9-108911140-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137573.
• BP7: Synonymous conserved (PhyloP=-0.192 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR gene

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.1230G>A	p.Pro410Pro	synonymous	Exon 12 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.888G>A	p.Pro296Pro	synonymous	Exon 12 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.183G>A	p.Pro61Pro	synonymous	Exon 10 of 35	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.1230G>A	p.Pro410Pro	synonymous	Exon 12 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.183G>A	p.Pro61Pro	synonymous	Exon 5 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.553-2736G>A		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1056 AN: 152042 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00806

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00733 AC: 1842 AN: 251410 AF XY: 0.00734

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.00853

Gnomad OTH exome AF: 0.00831

GnomAD4 exome AF: 0.00739 AC: 10801 AN: 1461858 Hom.: 53 Cov.: 32 AF XY: 0.00722 AC XY: 5254 AN XY: 727228

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.00347 AC: 155 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86256

European-Finnish (FIN) AF: 0.0283 AC: 1510 AN: 53418

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.00769 AC: 8546 AN: 1111986

Other (OTH) AF: 0.00628 AC: 379 AN: 60396

GnomAD4 genome AF: 0.00694 AC: 1056 AN: 152160 Hom.: 11 Cov.: 32 AF XY: 0.00809 AC XY: 602 AN XY: 74386

African (AFR) AF: 0.00149 AC: 62 AN: 41532

American (AMR) AF: 0.00517 AC: 79 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.0325 AC: 344 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00806 AC: 548 AN: 67992

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00597 Hom.: 4

Bravo AF: 0.00517

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00783

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	2	-	Familial dysautonomia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	4.8
DANN	Benign	0.55
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41278359;

hg19: chr9-111673420;