rs1140064

Variant names:

• chr9-108916228-C-T
• rs1140064
• NM_003640.5:c.934G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-108916228-C-T
• chr9-108916228-C-A
• chr9-108916228-C-G

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.934G>A​(p.Glu312Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0221 in 1,613,956 control chromosomes in the GnomAD database, including 478 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (43 hom., cov: 33)
  • Exomes 𝑓: 0.022 (435 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.65
• Publications: 17 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=0.0025151968).
• BP6: Variant 9-108916228-C-T is Benign according to our data. Variant chr9-108916228-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0211 (3212/152316) while in subpopulation NFE AF = 0.0247 (1678/68028). AF 95% confidence interval is 0.0237. There are 43 homozygotes in GnomAd4. There are 1576 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ELP1	NM_003640.5	MANE Select	c.934G>A	p.Glu312Lys	missense	Exon 10 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.592G>A	p.Glu198Lys	missense	Exon 10 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.-114G>A		5_prime_UTR	Exon 8 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.934G>A	p.Glu312Lys	missense	Exon 10 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.-114G>A		5_prime_UTR	Exon 3 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.552+6614G>A		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3200 AN: 152198 Hom.: 42 Cov.: 33

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0136

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0189 AC: 4765 AN: 251452 AF XY: 0.0192

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00737

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0243

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0223 AC: 32522 AN: 1461640 Hom.: 435 Cov.: 31 AF XY: 0.0215 AC XY: 15645 AN XY: 727138

African (AFR) AF: 0.0214 AC: 716 AN: 33480

American (AMR) AF: 0.00740 AC: 331 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 320 AN: 26132

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.00750 AC: 647 AN: 86252

European-Finnish (FIN) AF: 0.0238 AC: 1269 AN: 53418

Middle Eastern (MID) AF: 0.0107 AC: 62 AN: 5768

European-Non Finnish (NFE) AF: 0.0252 AC: 28029 AN: 1111784

Other (OTH) AF: 0.0189 AC: 1143 AN: 60388

GnomAD4 genome AF: 0.0211 AC: 3212 AN: 152316 Hom.: 43 Cov.: 33 AF XY: 0.0212 AC XY: 1576 AN XY: 74474

African (AFR) AF: 0.0226 AC: 941 AN: 41574

American (AMR) AF: 0.0136 AC: 208 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4824

European-Finnish (FIN) AF: 0.0238 AC: 253 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1678 AN: 68028

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0240 Hom.: 212

Bravo AF: 0.0200

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0270 AC: 104

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0226 AC: 194

ExAC AF: 0.0204 AC: 2483

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0240

EpiControl AF: 0.0202

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.6
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.048
Sift	Benign	0.36	T
Sift4G	Benign	0.50	T
Polyphen		0.075	B
Vest4		0.050
MPC		0.10
ClinPred		0.016	T
GERP RS		4.7
Varity_R		0.046
gMVP		0.18
Mutation Taster		=91/9	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: rs1140064; hg19: chr9-111678508;