Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_003640.5(ELP1):c.3876T>G(p.Thr1292Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,611,554 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1292T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 21 hom., cov: 33)

Exomes 𝑓: 0.015 ( 241 hom. )

Consequence

ELP1
NM_003640.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 0.360

Publications

8 publications found

Variant links:

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

ELP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 9-108874950-A-C is Benign according to our data. Variant chr9-108874950-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 364551.

BP7

Synonymous conserved (PhyloP=0.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0128 (1952/152370) while in subpopulation AMR AF = 0.0233 (356/15300). AF 95% confidence interval is 0.0213. There are 21 homozygotes in GnomAd4. There are 946 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR,AD 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELP1	NM_003640.5	MANE Select	c.3876T>G	p.Thr1292Thr	synonymous	Exon 36 of 37	NP_003631.2
ELP1	NM_001318360.2		c.3534T>G	p.Thr1178Thr	synonymous	Exon 36 of 37	NP_001305289.1
ELP1	NM_001330749.2		c.2829T>G	p.Thr943Thr	synonymous	Exon 34 of 35	NP_001317678.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ELP1	ENST00000374647.10	TSL:1 MANE Select	c.3876T>G	p.Thr1292Thr	synonymous	Exon 36 of 37	ENSP00000363779.5
ELP1	ENST00000537196.1	TSL:1	c.2829T>G	p.Thr943Thr	synonymous	Exon 29 of 30	ENSP00000439367.1
ELP1	ENST00000495759.6	TSL:1	n.*2486T>G		non_coding_transcript_exon	Exon 30 of 31	ENSP00000433514.2

Frequencies

GnomAD3 genomes

AF:

0.0128

AC:

1954

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00359

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0233

Gnomad ASJ

AF:

0.0484

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0130

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0146

AC:

3677

AN:

251358

AF XY:

0.0153

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0123

Gnomad ASJ exome

AF:

0.0542

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00408

Gnomad NFE exome

AF:

0.0176

Gnomad OTH exome

AF:

0.0183

GnomAD4 exome

AF:

0.0154

AC:

22541

AN:

1459184

Hom.:

241

Cov.:

AF XY:

0.0158

AC XY:

11472

AN XY:

726144

show subpopulations

African (AFR)

AF:

0.00332

AC:

111

AN:

33430

American (AMR)

AF:

0.0133

AC:

594

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0508

AC:

1327

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.0152

AC:

1308

AN:

86188

European-Finnish (FIN)

AF:

0.00407

AC:

217

AN:

53306

Middle Eastern (MID)

AF:

0.0498

AC:

287

AN:

5764

European-Non Finnish (NFE)

AF:

0.0159

AC:

17624

AN:

1109728

Other (OTH)

AF:

0.0178

AC:

1073

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1001

2002

3002

4003

5004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1952

AN:

152370

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

946

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00358

AC:

149

AN:

41590

American (AMR)

AF:

0.0233

AC:

356

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0484

AC:

168

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.0130

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0168

AC:

1143

AN:

68036

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

208

312

416

520

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0127

Hom.:

Bravo

AF:

0.0138

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0195

EpiControl

AF:

0.0212

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Familial dysautonomia (3)

ELP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

4.4

(source)

DANN

Benign

0.79

PhyloP100

0.36

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_003640.5:c.3876T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over