NM_003640.5:c.3473C>T

Variant names:

• chr9-108879545-G-A
• rs1538660
• NM_003640.5:c.3473C>T

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.3473C>T​(p.Pro1158Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,611,346 control chromosomes in the GnomAD database, including 28,307 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1158R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (4006 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24301 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.18
• Publications: 40 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=0.004501313).
• BP6: Variant 9-108879545-G-A is Benign according to our data. Variant chr9-108879545-G-A is described in ClinVar as Benign. ClinVar VariationId is 259113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 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.3473C>T	p.Pro1158Leu	missense	Exon 33 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.3131C>T	p.Pro1044Leu	missense	Exon 33 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.2426C>T	p.Pro809Leu	missense	Exon 31 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.3473C>T	p.Pro1158Leu	missense	Exon 33 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.2426C>T	p.Pro809Leu	missense	Exon 26 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*2083C>T		non_coding_transcript_exon	Exon 27 of 31	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33017 AN: 151832 Hom.: 4003 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.229

Gnomad FIN AF: 0.184

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.194 AC: 48749 AN: 250972 AF XY: 0.194

Gnomad AFR exome AF: 0.318

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.177 AC: 258332 AN: 1459392 Hom.: 24301 Cov.: 31 AF XY: 0.179 AC XY: 129759 AN XY: 726126

African (AFR) AF: 0.323 AC: 10799 AN: 33412

American (AMR) AF: 0.147 AC: 6574 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 5765 AN: 26120

East Asian (EAS) AF: 0.323 AC: 12823 AN: 39676

South Asian (SAS) AF: 0.223 AC: 19213 AN: 86214

European-Finnish (FIN) AF: 0.188 AC: 10032 AN: 53398

Middle Eastern (MID) AF: 0.185 AC: 1065 AN: 5760

European-Non Finnish (NFE) AF: 0.163 AC: 180606 AN: 1109802

Other (OTH) AF: 0.190 AC: 11455 AN: 60290

GnomAD4 genome AF: 0.217 AC: 33039 AN: 151954 Hom.: 4006 Cov.: 32 AF XY: 0.218 AC XY: 16182 AN XY: 74226

African (AFR) AF: 0.318 AC: 13170 AN: 41438

American (AMR) AF: 0.161 AC: 2462 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 772 AN: 3466

East Asian (EAS) AF: 0.293 AC: 1505 AN: 5140

South Asian (SAS) AF: 0.229 AC: 1101 AN: 4814

European-Finnish (FIN) AF: 0.184 AC: 1942 AN: 10536

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11358 AN: 67974

Other (OTH) AF: 0.197 AC: 416 AN: 2108

Alfa AF: 0.188 Hom.: 9054

Bravo AF: 0.220

TwinsUK AF: 0.160 AC: 594

ALSPAC AF: 0.172 AC: 663

ESP6500AA AF: 0.303 AC: 1333

ESP6500EA AF: 0.165 AC: 1423

ExAC AF: 0.198 AC: 24067

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial dysautonomia (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.79
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.2
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.045
Sift	Benign	0.72	T
Sift4G	Benign	0.82	T
Polyphen		0.0020	B
Vest4		0.084
MPC		0.074
ClinPred		0.0018	T
GERP RS		3.0
Varity_R		0.018
gMVP		0.43
Mutation Taster		=98/2	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: rs1538660; hg19: chr9-111641825; COSMIC: COSV65896197;