9-108912436-G-T

Variant names:

• chr9-108912436-G-T
• rs56053149
• NM_003640.5:c.1017C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003640.5(ELP1):​c.1017C>A​(p.Ser339Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,614,100 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S339S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (41 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.845
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060527623).
• BP6: Variant 9-108912436-G-T is Benign according to our data. Variant chr9-108912436-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 455950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000696 (106/152238) while in subpopulation SAS AF = 0.0213 (103/4828). AF 95% confidence interval is 0.018. There are 4 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003640.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.1017C>A	p.Ser339Arg	missense	Exon 11 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.675C>A	p.Ser225Arg	missense	Exon 11 of 37	NP_001305289.1
	ELP1	NM_001330749.2		c.-31C>A		5_prime_UTR	Exon 9 of 35	NP_001317678.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	ENST00000374647.10	TSL:1 MANE Select	c.1017C>A	p.Ser339Arg	missense	Exon 11 of 37	ENSP00000363779.5
	ELP1	ENST00000537196.1	TSL:1	c.-31C>A		5_prime_UTR	Exon 4 of 30	ENSP00000439367.1
	ELP1	ENST00000495759.6	TSL:1	n.553-4032C>A		intron	N/A	ENSP00000433514.2

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152120 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00282 AC: 709 AN: 251442 AF XY: 0.00395

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00149 AC: 2173 AN: 1461862 Hom.: 41 Cov.: 32 AF XY: 0.00218 AC XY: 1587 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0232 AC: 2003 AN: 86252

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000656 AC: 73 AN: 1111986

Other (OTH) AF: 0.00146 AC: 88 AN: 60396

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152238 Hom.: 4 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74444

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000321 Hom.: 3

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00335 AC: 407

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 08, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Familial dysautonomia Benign:2

Apr 19, 2018

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

not specified Benign:2

Aug 10, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 16, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.043
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.84
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.065	T
Sift4G	Benign	0.46	T
Polyphen		0.84	P
Vest4		0.40
MutPred		0.67		Gain of MoRF binding (P = 0.0211)
MVP		0.49
MPC		0.22
ClinPred		0.032	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.080
gMVP		0.27
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs56053149; hg19: chr9-111674716; COSMIC: COSV65898747;