rs2230792

Positions:

• chr9-108898571-C-G
• chr9-108898571-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003640.5(ELP1):​c.2294G>C​(p.Gly765Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G765E) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1558226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ELP1	NM_003640.5	c.2294G>C	p.Gly765Ala	missense_variant	22/37	ENST00000374647.10	NP_003631.2
ELP1	NM_001318360.2	c.1952G>C	p.Gly651Ala	missense_variant	22/37		NP_001305289.1
ELP1	NM_001330749.2	c.1247G>C	p.Gly416Ala	missense_variant	20/35		NP_001317678.1
ELP1	XM_047423991.1	c.2294G>C	p.Gly765Ala	missense_variant	22/25		XP_047279947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELP1	ENST00000374647.10	c.2294G>C	p.Gly765Ala	missense_variant	22/37	1	NM_003640.5	ENSP00000363779	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.25	T;T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.58	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.090
Sift	Benign	0.14	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.0040	B;.
Vest4		0.14
MutPred		0.39		Gain of ubiquitination at K761 (P = 0.1797);.;
MVP		0.21
MPC		0.097
ClinPred		0.28	T
GERP RS		4.0
Varity_R		0.098
gMVP		0.16

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230792; hg19: chr9-111660851;