9-108898571-C-T

Variant names:

• chr9-108898571-C-T
• rs2230792
• NM_003640.5:c.2294G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003640.5(ELP1):​c.2294G>A​(p.Gly765Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,601,350 control chromosomes in the GnomAD database, including 35,513 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G765G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5950 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29563 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.95
• Publications: 35 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: Orphanet, G2P
• 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=0.010578513).
• BP6: Variant 9-108898571-C-T is Benign according to our data. Variant chr9-108898571-C-T is described in ClinVar as Benign. ClinVar VariationId is 137577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.2294G>A	p.Gly765Glu	missense	Exon 22 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.1952G>A	p.Gly651Glu	missense	Exon 22 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.1247G>A	p.Gly416Glu	missense	Exon 20 of 35	NP_001317678.1	F5H2T0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	ENST00000374647.10	TSL:1 MANE Select	c.2294G>A	p.Gly765Glu	missense	Exon 22 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.1247G>A	p.Gly416Glu	missense	Exon 15 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*904G>A		non_coding_transcript_exon	Exon 16 of 31	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39333 AN: 151928 Hom.: 5943 Cov.: 32

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.229

GnomAD2 exomes AF: 0.221 AC: 55278 AN: 250044 AF XY: 0.213

Gnomad AFR exome AF: 0.423

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.0837

Gnomad EAS exome AF: 0.267

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.195 AC: 283107 AN: 1449300 Hom.: 29563 Cov.: 30 AF XY: 0.194 AC XY: 139959 AN XY: 721712

African (AFR) AF: 0.420 AC: 13864 AN: 33012

American (AMR) AF: 0.282 AC: 12598 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 2180 AN: 26078

East Asian (EAS) AF: 0.279 AC: 11004 AN: 39508

South Asian (SAS) AF: 0.195 AC: 16765 AN: 85920

European-Finnish (FIN) AF: 0.228 AC: 12137 AN: 53260

Middle Eastern (MID) AF: 0.127 AC: 685 AN: 5380

European-Non Finnish (NFE) AF: 0.184 AC: 202169 AN: 1101570

Other (OTH) AF: 0.195 AC: 11705 AN: 59934

GnomAD4 genome AF: 0.259 AC: 39376 AN: 152050 Hom.: 5950 Cov.: 32 AF XY: 0.260 AC XY: 19301 AN XY: 74356

African (AFR) AF: 0.413 AC: 17095 AN: 41440

American (AMR) AF: 0.238 AC: 3643 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 257 AN: 3470

East Asian (EAS) AF: 0.271 AC: 1401 AN: 5170

South Asian (SAS) AF: 0.216 AC: 1042 AN: 4820

European-Finnish (FIN) AF: 0.238 AC: 2520 AN: 10574

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12657 AN: 67974

Other (OTH) AF: 0.227 AC: 480 AN: 2114

Alfa AF: 0.209 Hom.: 9307

Bravo AF: 0.271

TwinsUK AF: 0.189 AC: 702

ALSPAC AF: 0.197 AC: 758

ESP6500AA AF: 0.414 AC: 1820

ESP6500EA AF: 0.182 AC: 1566

ExAC AF: 0.224 AC: 27142

Asia WGS AF: 0.263 AC: 912 AN: 3472

EpiCase AF: 0.174

EpiControl AF: 0.173

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Familial dysautonomia (4)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.16
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.9
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MPC		0.091
ClinPred		0.0027	T
GERP RS		4.0
Varity_R		0.10
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230792; hg19: chr9-111660851; COSMIC: COSV65898003;