dbSNP rs2230786: ELP1:p.Leu63Leu (chr9-108929883-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_003640.5(ELP1):c.189C>T(p.Leu63Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0216 in 1,613,842 control chromosomes in the GnomAD database, including 458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L63L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 32 hom., cov: 32)

Exomes 𝑓: 0.022 ( 426 hom. )

Consequence

ELP1
NM_003640.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0500

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

ELP1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003640.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 9-108929883-G-A is Benign according to our data. Variant chr9-108929883-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0179 (2732/152284) while in subpopulation NFE AF = 0.0246 (1674/68032). AF 95% confidence interval is 0.0236. There are 32 homozygotes in GnomAd4. There are 1339 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ELP1	NM_003640.5	MANE Select	c.189C>T	p.Leu63Leu	synonymous	Exon 3 of 37	NP_003631.2
ELP1	NM_001318360.2		c.-154C>T		5_prime_UTR	Exon 3 of 37	NP_001305289.1	A0A6Q8PGW3
ELP1	NM_001330749.2		c.-671C>T		5_prime_UTR	Exon 3 of 35	NP_001317678.1	F5H2T0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ELP1	ENST00000374647.10	TSL:1 MANE Select	c.189C>T	p.Leu63Leu	synonymous	Exon 3 of 37	ENSP00000363779.5	O95163
ELP1	ENST00000537196.1	TSL:1	c.-308+3981C>T		intron	N/A	ENSP00000439367.1	F5H2T0
ELP1	ENST00000495759.6	TSL:1	n.189C>T		non_coding_transcript_exon	Exon 3 of 31	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2723

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0117

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.0239

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0182

AC:

4566

AN:

251482

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.00650

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0243

Gnomad NFE exome

AF:

0.0279

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0220

AC:

32184

AN:

1461558

Hom.:

426

Cov.:

AF XY:

0.0213

AC XY:

15494

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0116

AC:

387

AN:

33472

American (AMR)

AF:

0.00653

AC:

292

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0123

AC:

321

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.00749

AC:

646

AN:

86236

European-Finnish (FIN)

AF:

0.0237

AC:

1268

AN:

53418

Middle Eastern (MID)

AF:

0.0108

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.0253

AC:

28099

AN:

1111976

Other (OTH)

AF:

0.0183

AC:

1106

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1666

3332

4997

6663

8329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1010

2020

3030

4040

5050

<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:

0.0179

AC:

2732

AN:

152284

Hom.:

Cov.:

AF XY:

0.0180

AC XY:

1339

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0119

AC:

494

AN:

41554

American (AMR)

AF:

0.0123

AC:

188

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00766

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0239

AC:

254

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0246

AC:

1674

AN:

68032

Other (OTH)

AF:

0.0142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

267

400

534

667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0185

Hom.:

Bravo

AF:

0.0167

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0239

EpiControl

AF:

0.0202

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Familial dysautonomia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.6

(source)

DANN

Benign

0.75

PhyloP100

0.050

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over