rs139703788

chr9-108911157-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003640.5(ELP1):c.1213C>T(p.Arg405Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000978 in 1,614,110 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R405Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (4 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037032366).
• BP6: Variant 9-108911157-G-A is Benign according to our data. Variant chr9-108911157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372384.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ELP1	NM_003640.5	c.1213C>T	p.Arg405Trp	missense_variant	12/37	ENST00000374647.10
ELP1	NM_001318360.2	c.871C>T	p.Arg291Trp	missense_variant	12/37
ELP1	NM_001330749.2	c.166C>T	p.Arg56Trp	missense_variant	10/35
ELP1	XM_047423991.1	c.1213C>T	p.Arg405Trp	missense_variant	12/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ELP1	ENST00000374647.10	c.1213C>T	p.Arg405Trp	missense_variant	12/37	1	NM_003640.5	P1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000879 AC: 221 AN: 251344 Hom.: 2 AF XY: 0.000883 AC XY: 120 AN XY: 135866

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00377

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00100 AC: 1462 AN: 1461818 Hom.: 4 Cov.: 32 AF XY: 0.000996 AC XY: 724 AN XY: 727218

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74462

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000799 AC: 97

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2019	This variant is associated with the following publications: (PMID: 26392352, 25203624) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2017	Variant summary: The IKBKAP c.1213C>T (p.Arg405Trp) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 236/277108 control chromosomes at a frequency of 0.0008517, which does not exceed the estimated maximal expected allele frequency of a pathogenic IKBKAP variant (0.001838). However, one subpopulation (Ashkenazi Jewish) has an allele frequency that is approximately 2 times above the maximal expected allele frequency, and two homozygous controls individuals of South Asian descent have been identified, suggesting a benign impact for the variant. One clinical diagnostic laboratories/reputable databases classified this variant as one of uncertain significance. Taken together, this variant is classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial dysautonomia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary sensory and autonomic neuropathy Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.31
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Pathogenic	3.5	M;.
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.55
MVP		0.75
MPC		0.41
ClinPred		0.12	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.22
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs139703788; hg19: chr9-111673437;