9-108902935-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.437

Publications

7 publications found

Variant links:

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: G2P, Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ELP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ELP1	NM_003640.5 link	c.1758T>G	p.Pro586Pro	synonymous_variant	Exon 16 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2 link	c.1416T>G	p.Pro472Pro	synonymous_variant	Exon 16 of 37		NP_001305289.1
ELP1	NM_001330749.2 link	c.711T>G	p.Pro237Pro	synonymous_variant	Exon 14 of 35		NP_001317678.1
ELP1	XM_047423991.1 link	c.1758T>G	p.Pro586Pro	synonymous_variant	Exon 16 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.1758T>G	p.Pro586Pro	synonymous_variant	Exon 16 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes

AF:

0.00951

AC:

1448

AN:

152232

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0169

AC XY:

12282

AN XY:

726800

show subpopulations

African (AFR)

AF:

0.00203

AC:

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:

AN:

39694

South Asian (SAS)

AF:

0.0612

AC:

5274

AN:

86184

European-Finnish (FIN)

AF:

0.00144

AC:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

974

1949

2923

3898

4872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00950

AC:

1447

AN:

152350

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

706

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41584

American (AMR)

AF:

0.00921

AC:

141

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

AN:

3470

East Asian (EAS)

AF:

0.000965

AC:

AN:

5184

South Asian (SAS)

AF:

0.0553

AC:

267

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0123

AC:

835

AN:

68034

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.00849

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 22, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The IKBKAP c.1758T>G (p.Pro586Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1977/119930 control chromosomes (50 homozygotes) at a frequency of 0.0164846, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic IKBKAP variant (0.001838), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign and another lab classified it as uncertain significance, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial dysautonomia

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 10, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

4.4

(source)

DANN

Benign

0.52

PhyloP100

-0.44

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over