Genetic Variant ELP4:p.Tyr91Phe (chr11-31539674-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_019040.5(ELP4):c.272A>T(p.Tyr91Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. Y91C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ELP4
NM_019040.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.17

Publications

0 publications found

Variant links:

Genes affected

ELP4 (HGNC:1171): (elongator acetyltransferase complex subunit 4) This gene encodes a component of the six subunit elongator complex, a histone acetyltransferase complex that associates directly with RNA polymerase II during transcriptional elongation. The human gene can partially complement sensitivity phenotypes of yeast ELP4 deletion mutants. This gene has also been associated with Rolandic epilepsy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ELP4 Gene-Disease associations (from GenCC):

aniridia 2
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Genomics England PanelApp
aniridia 1
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ELP4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-31539674-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1328942.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.30604115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP4	NM_019040.5 link	c.272A>T	p.Tyr91Phe	missense_variant	Exon 3 of 10	ENST00000640961.2	NP_061913.3	Q96EB1-1
ELP4	NM_001288726.2 link	c.272A>T	p.Tyr91Phe	missense_variant	Exon 3 of 12		NP_001275655.1	Q96EB1G5E9D4
ELP4	NM_001288725.2 link	c.272A>T	p.Tyr91Phe	missense_variant	Exon 3 of 11		NP_001275654.1	Q96EB1-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP4	ENST00000640961.2 link	c.272A>T	p.Tyr91Phe	missense_variant	Exon 3 of 10	1	NM_019040.5	ENSP00000492152.1		Q96EB1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453764

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33244

American (AMR)

AF:

0.00

AC:

AN:

43616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25968

East Asian (EAS)

AF:

0.00

AC:

AN:

39472

South Asian (SAS)

AF:

0.00

AC:

AN:

83764

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108594

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.027

T;.;.;.;.;.;.;.;.;.;.;.

Eigen

Benign

0.070

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.0070

MetaRNN

Benign

0.31

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

L;.;L;.;.;.;.;.;.;.;.;.

PhyloP100

5.2

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

.;.;N;.;N;.;.;.;.;.;.;N

REVEL

Benign

0.14

Sift

Benign

0.33

.;.;T;.;T;.;.;.;.;.;.;T

Sift4G

Benign

0.21

.;.;T;.;T;.;.;.;.;.;.;T

Polyphen

0.49

P;.;.;.;.;.;.;.;.;.;.;P

Vest4

0.38, 0.21, 0.20

MutPred

0.61

Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);Loss of ubiquitination at K90 (P = 0.092);

MVP

0.54

MPC

0.10

ClinPred

0.74

GERP RS

5.3

Varity_R

0.23

gMVP

0.40

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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11-31539674-A-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over