Variant 6-100512904-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_006828.4(ASCC3):c.6090A>C(p.Leu2030Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,404 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

ASCC3
NM_006828.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.218

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ASCC3. . Gene score misZ 2.2287 (greater than the threshold 3.09). Trascript score misZ 3.3318 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability.

BP4

Computational evidence support a benign effect (MetaRNN=0.28457206).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASCC3	NM_006828.4 linkuse as main transcript	c.6090A>C	p.Leu2030Phe	missense_variant	40/42	ENST00000369162.7	NP_006819.2	Q8N3C0-1B4DR60

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASCC3	ENST00000369162.7 linkuse as main transcript	c.6090A>C	p.Leu2030Phe	missense_variant	40/42	5	NM_006828.4	ENSP00000358159.2		Q8N3C0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250912

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135628

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000262

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461404

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000255

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 07, 2018

The L2030F variant in the ASCC3 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L2030F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L2030F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. As an alternate mechanism, splice predictor models suggest that L2030F may enhance the cryptic splicing acceptor site in exon 40, which may result in abnormal gene splicing. We interpret L2030F as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.030

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-2.0

REVEL

Benign

0.24

Sift

Benign

0.063

Sift4G

Benign

0.070

Polyphen

0.41

Vest4

0.38

MutPred

0.75

Gain of sheet (P = 0.0477);

MVP

0.49

MPC

0.56

ClinPred

0.40

GERP RS

-1.3

Varity_R

0.26

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over