9-108880095-C-G

Position:

chr9-108880095-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003640.5(ELP1):c.3417G>C(p.Leu1139Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

ELP1
NM_003640.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.911

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050576597).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ELP1	NM_003640.5 linkuse as main transcript	c.3417G>C	p.Leu1139Phe	missense_variant	32/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2 linkuse as main transcript	c.3075G>C	p.Leu1025Phe	missense_variant	32/37		NP_001305289.1
ELP1	NM_001330749.2 linkuse as main transcript	c.2370G>C	p.Leu790Phe	missense_variant	30/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10 linkuse as main transcript	c.3417G>C	p.Leu1139Phe	missense_variant	32/37	1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152204

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251446

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.000589

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000206

AC:

301

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

131

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.000226

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000118

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000128

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000527

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 05, 2022	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1139 of the ELP1 protein (p.Leu1139Phe). This variant is present in population databases (rs202080366, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 455965). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.3417G>C (p.L1139F) alteration is located in exon 32 (coding exon 31) of the IKBKAP gene. This alteration results from a G to C substitution at nucleotide position 3417, causing the leucine (L) at amino acid position 1139 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial dysautonomia;C0025149:Medulloblastoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.24

DEOGEN2

Benign

0.087

T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.76

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

0.89

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.83

N;N

REVEL

Benign

0.071

Sift

Benign

0.72

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.67

P;.

Vest4

0.21

MutPred

0.31

Gain of methylation at K1136 (P = 0.1137);.;

MVP

0.49

MPC

0.15

ClinPred

0.046

GERP RS

3.2

Varity_R

0.028

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over