Genetic Variant ELP6:p.Ser89Cys (chr3-47504387-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001031703.3(ELP6):c.266C>G(p.Ser89Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ELP6
NM_001031703.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.66

Publications

0 publications found

Variant links:

Genes affected

ELP6 (HGNC:25976): (elongator acetyltransferase complex subunit 6) Predicted to be involved in positive regulation of cell migration. Located in cytosol and nucleus. Part of elongator holoenzyme complex. [provided by Alliance of Genome Resources, Apr 2022]

ELP6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP6	NM_001031703.3 link	c.266C>G	p.Ser89Cys	missense_variant	Exon 4 of 7	ENST00000296149.9	NP_001026873.2	Q0PNE2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ELP6	ENST00000296149.9 link	c.266C>G	p.Ser89Cys	missense_variant	Exon 4 of 7	1	NM_001031703.3	ENSP00000296149.4		Q0PNE2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725388

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

44368

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.00

AC:

AN:

85554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110200

Other (OTH)

AF:

0.00

AC:

AN:

60234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.266C>G (p.S89C) alteration is located in exon 4 (coding exon 4) of the ELP6 gene. This alteration results from a C to G substitution at nucleotide position 266, causing the serine (S) at amino acid position 89 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.027

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

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;.;D;D;D;D;D;D

M_CAP

Benign

0.0098

MetaRNN

Uncertain

0.59

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

MetaSVM

Uncertain

-0.17

MutationAssessor

Uncertain

2.7

M;.;.;.;.;.;.;.

PhyloP100

5.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;D

REVEL

Uncertain

0.30

Sift

Benign

0.15

T;T;T;T;T;D;D;D

Sift4G

Benign

0.20

T;T;T;.;D;.;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.59

MutPred

0.67

Gain of methylation at K88 (P = 0.0367);.;.;.;.;.;.;.;

MVP

0.74

MPC

1.1

ClinPred

0.63

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.31

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over