Genetic Variant ELP1:p.Met1? (chr9-108912403-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001330749.2(ELP1):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

ELP1
NM_001330749.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.145

Publications

1 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

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 64 codons. Genomic position: 108911133. Lost 0.064 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330749.2. 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.1050G>A	p.Met350Ile	missense	Exon 11 of 37	NP_003631.2
ELP1	NM_001330749.2		c.3G>A	p.Met1?	start_lost	Exon 9 of 35	NP_001317678.1	F5H2T0
ELP1	NM_001318360.2		c.708G>A	p.Met236Ile	missense	Exon 11 of 37	NP_001305289.1	A0A6Q8PGW3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ELP1	ENST00000537196.1	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 4 of 30	ENSP00000439367.1	F5H2T0
ELP1	ENST00000374647.10	TSL:1 MANE Select	c.1050G>A	p.Met350Ile	missense	Exon 11 of 37	ENSP00000363779.5	O95163
ELP1	ENST00000495759.6	TSL:1	n.553-3999G>A		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial dysautonomia (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.044

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.53

M_CAP

Benign

0.010

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.14

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.87

REVEL

Benign

0.054

Sift

Benign

0.50

Sift4G

Benign

0.48

Polyphen

0.0

Vest4

0.12

MutPred

0.53

Gain of methylation at K345 (P = 0.0752)

MVP

0.28

MPC

0.078

ClinPred

0.077

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.023

gMVP

0.20

Mutation Taster

=16/184

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over