Genetic Variant NM_001031703.3:c.403C>T (chr3-47501772-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001031703.3(ELP6):c.403C>T(p.Arg135Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R135P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ELP6
NM_001031703.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.190

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15617329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ELP6	NM_001031703.3 link	c.403C>T	p.Arg135Trp	missense_variant	Exon 5 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.403C>T	p.Arg135Trp	missense_variant	Exon 5 of 7	1	NM_001031703.3	ENSP00000296149.4		Q0PNE2-1

Frequencies

GnomAD3 genomes

AF:

0.00000677

AC:

AN:

147670

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000281

AC:

AN:

249462

AF XY:

0.0000296

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000719

AC:

AN:

1111928

Other (OTH)

AF:

0.00

AC:

AN:

60392

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

AF:

0.00000677

AC:

AN:

147670

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39926

American (AMR)

AF:

0.00

AC:

AN:

14846

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3396

East Asian (EAS)

AF:

0.00

AC:

AN:

4954

South Asian (SAS)

AF:

0.00

AC:

AN:

4576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10432

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66354

Other (OTH)

AF:

0.00

AC:

AN:

2012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.403C>T (p.R135W) alteration is located in exon 5 (coding exon 5) of the ELP6 gene. This alteration results from a C to T substitution at nucleotide position 403, causing the arginine (R) at amino acid position 135 to be replaced by a tryptophan (W). 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

Benign

-0.25

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

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

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.64

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

M_CAP

Benign

0.0048

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

PhyloP100

0.19

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.8

N;N;N;N;N;N;N;N

REVEL

Benign

0.11

Sift

Uncertain

0.016

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

Sift4G

Uncertain

0.017

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

Polyphen

0.95

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

Vest4

0.20

MutPred

0.39

Loss of disorder (P = 0.0484);.;.;.;.;.;.;.;

MVP

0.47

MPC

0.50

ClinPred

0.062

GERP RS

-1.6

Varity_R

0.053

gMVP

0.24

Mutation Taster

=94/6

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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NM_001031703.3:c.403C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over