chr9-108867764-G-T

Variant names:

• chr9-108867764-G-T
• rs4978371
• ENST00000495759.6:n.*3960C>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.*1351C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 152,074 control chromosomes in the GnomAD database, including 15,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (15237 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ELP1 NM_003640.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.00
• Publications: 9 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 (BayesDel_noAF=-0.94).
• BP6: Variant 9-108867764-G-T is Benign according to our data. Variant chr9-108867764-G-T is described in ClinVar as [Benign]. Clinvar id is 364536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP1	NM_003640.5	c.*1351C>A		3_prime_UTR_variant	Exon 37 of 37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.*1351C>A		3_prime_UTR_variant	Exon 37 of 37		NP_001305289.1
ELP1	NM_001330749.2	c.*1351C>A		3_prime_UTR_variant	Exon 35 of 35		NP_001317678.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.*1351C>A		3_prime_UTR_variant	Exon 37 of 37	1	NM_003640.5	ENSP00000363779.5

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62277 AN: 151956 Hom.: 15221 Cov.: 33

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.366

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.410 AC: 62329 AN: 152074 Hom.: 15237 Cov.: 33 AF XY: 0.410 AC XY: 30512 AN XY: 74332

African (AFR) AF: 0.690 AC: 28638 AN: 41496

American (AMR) AF: 0.348 AC: 5322 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 883 AN: 3466

East Asian (EAS) AF: 0.404 AC: 2094 AN: 5178

South Asian (SAS) AF: 0.306 AC: 1476 AN: 4824

European-Finnish (FIN) AF: 0.358 AC: 3776 AN: 10540

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18986 AN: 67974

Other (OTH) AF: 0.362 AC: 764 AN: 2110

Alfa AF: 0.352 Hom.: 2683

Bravo AF: 0.427

Asia WGS AF: 0.394 AC: 1370 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial dysautonomia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.7
DANN	Benign	0.24
PhyloP100		1.0
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: rs4978371; hg19: chr9-111630044;