Genetic Variant ELP1:p.Leu752Val (chr9-108898700-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_003640.5(ELP1):c.2254C>G(p.Leu752Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,612,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L752I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.94

Publications

2 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5 link	c.2254C>G	p.Leu752Val	missense_variant	Exon 21 of 37	ENST00000374647.10	NP_003631.2	O95163Q4LE38Q8N516
ELP1	NM_001318360.2 link	c.1912C>G	p.Leu638Val	missense_variant	Exon 21 of 37		NP_001305289.1	O95163A0A6Q8PGW3B4E3I9
ELP1	NM_001330749.2 link	c.1207C>G	p.Leu403Val	missense_variant	Exon 19 of 35		NP_001317678.1	F5H2T0B3KNB2
ELP1	XM_047423991.1 link	c.2254C>G	p.Leu752Val	missense_variant	Exon 21 of 25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 link	c.2254C>G	p.Leu752Val	missense_variant	Exon 21 of 37	1	NM_003640.5	ENSP00000363779.5		O95163

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250966

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460462

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39640

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53096

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111180

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000657

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.39

MutationAssessor

Pathogenic

3.0

M;.

PhyloP100

9.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.51

Sift

Uncertain

0.013

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.62

MPC

0.42

ClinPred

0.97

GERP RS

5.3

Varity_R

0.47

gMVP

0.49

Mutation Taster

=54/46

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over