9-108922849-A-T

Position:

• chr9-108922849-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003640.5(ELP1):​c.545T>A​(p.Met182Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,613,242 control chromosomes in the GnomAD database, including 1,875 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (935 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (940 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.16

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010724664).
• BP6: Variant 9-108922849-A-T is Benign according to our data. Variant chr9-108922849-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 259114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-108922849-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.545T>A	p.Met182Lys	missense_variant	6/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.203T>A	p.Met68Lys	missense_variant	6/37		NP_001305289.1
ELP1	XM_047423991.1	c.545T>A	p.Met182Lys	missense_variant	6/25		XP_047279947.1
ELP1	NM_001330749.2	c.-315T>A		5_prime_UTR_variant	6/35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.545T>A	p.Met182Lys	missense_variant	6/37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9152 AN: 152144 Hom.: 935 Cov.: 33

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0415

GnomAD3 exomes AF: 0.0156 AC: 3928 AN: 251422 Hom.: 379 AF XY: 0.0110 AC XY: 1488 AN XY: 135884

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00607 AC: 8868 AN: 1460980 Hom.: 940 Cov.: 31 AF XY: 0.00515 AC XY: 3747 AN XY: 726886

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.00923

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000336

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000122

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0602 AC: 9171 AN: 152262 Hom.: 935 Cov.: 33 AF XY: 0.0579 AC XY: 4314 AN XY: 74464

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.00934 Hom.: 112

Bravo AF: 0.0691

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.213 AC: 940

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0197 AC: 2393

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2022	- -

Familial dysautonomia Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Benign	0.67
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.99	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.070
Sift	Benign	0.38	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.11
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.21
gMVP		0.21

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

Other links and lift over

dbSNP: rs10521092; hg19: chr9-111685129;