9-108917592-G-A

Variant names:

• chr9-108917592-G-A
• rs12340246
• NM_003640.5:c.819C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003640.5(ELP1):​c.819C>T​(p.Leu273Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0527 in 1,613,602 control chromosomes in the GnomAD database, including 3,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L273L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.051 (313 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2936 hom.)
• Consequence: ELP1 NM_003640.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.861
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-108917592-G-A is Benign according to our data. Variant chr9-108917592-G-A is described in ClinVar as Benign. ClinVar VariationId is 137570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.861 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 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.819C>T	p.Leu273Leu	synonymous	Exon 9 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.477C>T	p.Leu159Leu	synonymous	Exon 9 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.-229C>T		5_prime_UTR	Exon 7 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.819C>T	p.Leu273Leu	synonymous	Exon 9 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.-229C>T		5_prime_UTR	Exon 2 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.552+5250C>T		intron	N/A	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.0513 AC: 7806 AN: 152050 Hom.: 311 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0555

Gnomad FIN AF: 0.0971

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0485

Gnomad OTH AF: 0.0566

GnomAD2 exomes AF: 0.0733 AC: 18430 AN: 251476 AF XY: 0.0673

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.119

Gnomad FIN exome AF: 0.0968

Gnomad NFE exome AF: 0.0444

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0528 AC: 77165 AN: 1461432 Hom.: 2936 Cov.: 33 AF XY: 0.0514 AC XY: 37397 AN XY: 727048

African (AFR) AF: 0.0120 AC: 401 AN: 33474

American (AMR) AF: 0.193 AC: 8652 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 430 AN: 26130

East Asian (EAS) AF: 0.121 AC: 4819 AN: 39690

South Asian (SAS) AF: 0.0432 AC: 3727 AN: 86252

European-Finnish (FIN) AF: 0.0908 AC: 4850 AN: 53418

Middle Eastern (MID) AF: 0.0333 AC: 192 AN: 5768

European-Non Finnish (NFE) AF: 0.0459 AC: 51004 AN: 1111608

Other (OTH) AF: 0.0512 AC: 3090 AN: 60370

GnomAD4 genome AF: 0.0513 AC: 7810 AN: 152170 Hom.: 313 Cov.: 32 AF XY: 0.0550 AC XY: 4092 AN XY: 74384

African (AFR) AF: 0.0138 AC: 574 AN: 41526

American (AMR) AF: 0.119 AC: 1818 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3470

East Asian (EAS) AF: 0.120 AC: 619 AN: 5160

South Asian (SAS) AF: 0.0547 AC: 264 AN: 4828

European-Finnish (FIN) AF: 0.0971 AC: 1027 AN: 10574

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0485 AC: 3299 AN: 68008

Other (OTH) AF: 0.0555 AC: 117 AN: 2108

Alfa AF: 0.0453 Hom.: 445

Bravo AF: 0.0544

Asia WGS AF: 0.0860 AC: 298 AN: 3478

EpiCase AF: 0.0419

EpiControl AF: 0.0431

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.4
DANN	Benign	0.69
PhyloP100		0.86
Mutation Taster		=100/0	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: rs12340246; hg19: chr9-111679872; COSMIC: COSV65896328;