Genetic Variant ASCC3:p.Tyr2176Cys (chr6-100509468-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006828.4(ASCC3):c.6527A>G(p.Tyr2176Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0609 in 1,614,024 control chromosomes in the GnomAD database, including 4,308 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.10 ( 1147 hom., cov: 32)

Exomes 𝑓: 0.057 ( 3161 hom. )

Consequence

ASCC3
NM_006828.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.70

Publications

28 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017665625).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCC3	NM_006828.4 link	c.6527A>G	p.Tyr2176Cys	missense_variant	Exon 42 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.6527A>G	p.Tyr2176Cys	missense_variant	Exon 42 of 42	5	NM_006828.4	ENSP00000358159.2		Q8N3C0-1
ASCC3	ENST00000518006.1 link	n.443A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15356

AN:

152168

Hom.:

1144

Cov.:

show subpopulations

Gnomad AFR

AF:

0.207

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0831

Gnomad ASJ

AF:

0.0260

Gnomad EAS

AF:

0.145

Gnomad SAS

AF:

0.0763

Gnomad FIN

AF:

0.0666

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0494

Gnomad OTH

AF:

0.0888

GnomAD2 exomes

AF:

0.0796

AC:

20014

AN:

251438

AF XY:

0.0753

show subpopulations

Gnomad AFR exome

AF:

0.211

Gnomad AMR exome

AF:

0.0986

Gnomad ASJ exome

AF:

0.0291

Gnomad EAS exome

AF:

0.159

Gnomad FIN exome

AF:

0.0637

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0727

GnomAD4 exome

AF:

0.0568

AC:

82961

AN:

1461738

Hom.:

3161

Cov.:

AF XY:

0.0570

AC XY:

41472

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.212

AC:

7085

AN:

33480

American (AMR)

AF:

0.0999

AC:

4469

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0280

AC:

733

AN:

26136

East Asian (EAS)

AF:

0.131

AC:

5182

AN:

39700

South Asian (SAS)

AF:

0.0764

AC:

6589

AN:

86252

European-Finnish (FIN)

AF:

0.0624

AC:

3333

AN:

53418

Middle Eastern (MID)

AF:

0.0747

AC:

430

AN:

5758

European-Non Finnish (NFE)

AF:

0.0460

AC:

51190

AN:

1111882

Other (OTH)

AF:

0.0654

AC:

3950

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

4302

8604

12905

17207

21509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2070

4140

6210

8280

10350

<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:

0.101

AC:

15376

AN:

152286

Hom.:

1147

Cov.:

AF XY:

0.0997

AC XY:

7423

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.207

AC:

8601

AN:

41544

American (AMR)

AF:

0.0831

AC:

1272

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

AN:

3468

East Asian (EAS)

AF:

0.145

AC:

754

AN:

5188

South Asian (SAS)

AF:

0.0767

AC:

370

AN:

4822

European-Finnish (FIN)

AF:

0.0666

AC:

707

AN:

10612

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0495

AC:

3365

AN:

68024

Other (OTH)

AF:

0.0865

AC:

183

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

687

1373

2060

2746

3433

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0655

Hom.:

2141

Bravo

AF:

0.107

TwinsUK

AF:

0.0423

AC:

157

ALSPAC

AF:

0.0470

AC:

181

ESP6500AA

AF:

0.195

AC:

860

ESP6500EA

AF:

0.0463

AC:

398

ExAC

AF:

0.0820

AC:

9959

Asia WGS

AF:

0.123

AC:

429

AN:

3478

EpiCase

AF:

0.0550

EpiControl

AF:

0.0530

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.053

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.94

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.5

PhyloP100

3.7

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Benign

0.18

Sift4G

Benign

0.13

Polyphen

0.54

Vest4

0.14

MPC

0.31

ClinPred

0.042

GERP RS

4.8

Varity_R

0.15

gMVP

0.39

Mutation Taster

=84/16

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over