Genetic Variant ASCC3:p.Glu59Ala (chr6-100864129-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_006828.4(ASCC3):c.176A>C(p.Glu59Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ASCC3
NM_006828.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.31

Publications

3 publications found

Variant links:

Genes affected

ASCC3 (HGNC:18697): (activating signal cointegrator 1 complex subunit 3) This gene encodes a protein that belongs to a family of helicases that are involved in the ATP-dependent unwinding of nucleic acid duplexes. The encoded protein is the largest subunit of the activating signal cointegrator 1 complex that is involved in DNA repair and resistance to alkylation damage. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ASCC3 Gene-Disease associations (from GenCC):

intellectual developmental disorder, autosomal recessive 81
Inheritance: AR Classification: LIMITED Submitted by: G2P
intellectual disability
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ASCC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25111485).

BP6

Variant 6-100864129-T-G is Benign according to our data. Variant chr6-100864129-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 522895.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCC3	NM_006828.4 link	c.176A>C	p.Glu59Ala	missense_variant	Exon 3 of 42	ENST00000369162.7	NP_006819.2	Q8N3C0-1B4DR60

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCC3	ENST00000369162.7 link	c.176A>C	p.Glu59Ala	missense_variant	Exon 3 of 42	5	NM_006828.4	ENSP00000358159.2		Q8N3C0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453602

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33308

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39546

South Asian (SAS)

AF:

0.00

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51628

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106426

Other (OTH)

AF:

0.00

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

T;.;T;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Benign

0.0091

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

L;L;.;L

PhyloP100

5.3

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.99

N;N;D;D

REVEL

Benign

0.10

Sift

Benign

0.20

T;T;T;D

Sift4G

Benign

0.65

T;T;.;T

Polyphen

0.043

B;.;.;.

Vest4

0.27

MutPred

0.41

Gain of MoRF binding (P = 0.0303);Gain of MoRF binding (P = 0.0303);Gain of MoRF binding (P = 0.0303);Gain of MoRF binding (P = 0.0303);

MVP

0.38

MPC

0.27

ClinPred

0.78

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.19

Mutation Taster

=67/33

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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6-100864129-T-G

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