rs3204145

Variant names:

• chr9-108889340-A-T
• rs3204145
• NM_003640.5:c.3214T>A

Your query was ambiguous. Multiple possible variants found:

• chr9-108889340-A-T
• chr9-108889340-A-G

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.3214T>A​(p.Cys1072Ser) variant causes a missense change. The variant allele was found at a frequency of 0.181 in 1,613,288 control chromosomes in the GnomAD database, including 28,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. C1072F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.22 (4012 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24310 hom.)
• Consequence: ELP1 NM_003640.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.72
• Publications: 44 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=0.003656298).
• BP6: Variant 9-108889340-A-T is Benign according to our data. Variant chr9-108889340-A-T is described in ClinVar as Benign. ClinVar VariationId is 259112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 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.3214T>A	p.Cys1072Ser	missense	Exon 29 of 37	NP_003631.2
	ELP1	NM_001318360.2		c.2872T>A	p.Cys958Ser	missense	Exon 29 of 37	NP_001305289.1	A0A6Q8PGW3
	ELP1	NM_001330749.2		c.2167T>A	p.Cys723Ser	missense	Exon 27 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.3214T>A	p.Cys1072Ser	missense	Exon 29 of 37	ENSP00000363779.5	O95163
	ELP1	ENST00000537196.1	TSL:1	c.2167T>A	p.Cys723Ser	missense	Exon 22 of 30	ENSP00000439367.1	F5H2T0
	ELP1	ENST00000495759.6	TSL:1	n.*1824T>A		non_coding_transcript_exon	Exon 23 of 31	ENSP00000433514.2	H0YDF3

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33060 AN: 151902 Hom.: 4009 Cov.: 32

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.226

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.199

GnomAD2 exomes AF: 0.194 AC: 48834 AN: 251268 AF XY: 0.194

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.288

Gnomad FIN exome AF: 0.187

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.177 AC: 259093 AN: 1461268 Hom.: 24310 Cov.: 32 AF XY: 0.179 AC XY: 130100 AN XY: 726934

African (AFR) AF: 0.325 AC: 10876 AN: 33464

American (AMR) AF: 0.147 AC: 6569 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5825 AN: 26132

East Asian (EAS) AF: 0.323 AC: 12834 AN: 39692

South Asian (SAS) AF: 0.223 AC: 19236 AN: 86242

European-Finnish (FIN) AF: 0.188 AC: 10032 AN: 53412

Middle Eastern (MID) AF: 0.186 AC: 1070 AN: 5768

European-Non Finnish (NFE) AF: 0.163 AC: 181163 AN: 1111470

Other (OTH) AF: 0.190 AC: 11488 AN: 60370

GnomAD4 genome AF: 0.218 AC: 33083 AN: 152020 Hom.: 4012 Cov.: 32 AF XY: 0.218 AC XY: 16215 AN XY: 74322

African (AFR) AF: 0.319 AC: 13222 AN: 41436

American (AMR) AF: 0.160 AC: 2447 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 783 AN: 3468

East Asian (EAS) AF: 0.293 AC: 1516 AN: 5170

South Asian (SAS) AF: 0.229 AC: 1104 AN: 4814

European-Finnish (FIN) AF: 0.183 AC: 1939 AN: 10572

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

European-Non Finnish (NFE) AF: 0.167 AC: 11342 AN: 67970

Other (OTH) AF: 0.197 AC: 417 AN: 2112

Alfa AF: 0.182 Hom.: 2075

Bravo AF: 0.220

TwinsUK AF: 0.160 AC: 595

ALSPAC AF: 0.173 AC: 665

ESP6500AA AF: 0.304 AC: 1341

ESP6500EA AF: 0.165 AC: 1423

ExAC AF: 0.198 AC: 24083

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
-	-	4	Familial dysautonomia (4)
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.087
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.19	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PhyloP100		6.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.11
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.0	B
Vest4		0.17
MutPred		0.50		Gain of disorder (P = 0.001)
MPC		0.086
ClinPred		0.020	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.55
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: rs3204145; hg19: chr9-111651620; COSMIC: COSV65897440;