rs35054425

Variant names:

• chr9-108902935-A-C
• rs35054425
• NM_003640.5:c.1758T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-108902935-A-C
• chr9-108902935-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003640.5(ELP1):​c.1758T>G​(p.Pro586Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,613,206 control chromosomes in the GnomAD database, including 388 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (10 hom., cov: 32)
  • Exomes 𝑓: 0.015 (378 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.437
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-108902935-A-C is Benign according to our data. Variant chr9-108902935-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 364572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

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.1758T>G	p.Pro586Pro	synonymous	Exon 16 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.1416T>G	p.Pro472Pro	synonymous	Exon 16 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.711T>G	p.Pro237Pro	synonymous	Exon 14 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.1758T>G	p.Pro586Pro	synonymous	Exon 16 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.711T>G	p.Pro237Pro	synonymous	Exon 9 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*368T>G		non_coding_transcript_exon	Exon 10 of 31	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.00951 AC: 1448 AN: 152232 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0553

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0123

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.0158 AC: 3961 AN: 251174 AF XY: 0.0186

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.0153 AC: 22339 AN: 1460856 Hom.: 378 Cov.: 30 AF XY: 0.0169 AC XY: 12282 AN XY: 726800

African (AFR) AF: 0.00203 AC: 68 AN: 33448

American (AMR) AF: 0.00658 AC: 294 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 599 AN: 26120

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0612 AC: 5274 AN: 86184

European-Finnish (FIN) AF: 0.00144 AC: 77 AN: 53418

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5766

European-Non Finnish (NFE) AF: 0.0134 AC: 14875 AN: 1111152

Other (OTH) AF: 0.0161 AC: 972 AN: 60360

GnomAD4 genome AF: 0.00950 AC: 1447 AN: 152350 Hom.: 10 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74508

African (AFR) AF: 0.00207 AC: 86 AN: 41584

American (AMR) AF: 0.00921 AC: 141 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0553 AC: 267 AN: 4824

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0123 AC: 835 AN: 68034

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0108 Hom.: 10

Bravo AF: 0.00849

Asia WGS AF: 0.0260 AC: 90 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	Familial dysautonomia (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	4.4
DANN	Benign	0.52
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35054425; hg19: chr9-111665215; COSMIC: COSV107487492;