rs240768

Variant names:

• chr6-100509468-T-C
• rs240768
• NM_006828.4:c.6527A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (1147 hom., cov: 32)
  • Exomes 𝑓: 0.057 (3161 hom.)
• Consequence: ASCC3 NM_006828.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.70

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]

ACMG classification

Verdict is Benign. Variant got -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	c.6527A>G	p.Tyr2176Cys	missense_variant	Exon 42 of 42	ENST00000369162.7	NP_006819.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCC3	ENST00000369162.7	c.6527A>G	p.Tyr2176Cys	missense_variant	Exon 42 of 42	5	NM_006828.4	ENSP00000358159.2
ASCC3	ENST00000518006.1	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.: 32

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

GnomAD3 exomes AF: 0.0796 AC: 20014 AN: 251438 Hom.: 1152 AF XY: 0.0753 AC XY: 10235 AN XY: 135908

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 SAS exome AF: 0.0777

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.: 31 AF XY: 0.0570 AC XY: 41472 AN XY: 727182

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.0999

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.0764

Gnomad4 FIN exome AF: 0.0624

Gnomad4 NFE exome AF: 0.0460

Gnomad4 OTH exome AF: 0.0654

GnomAD4 genome AF: 0.101 AC: 15376 AN: 152286 Hom.: 1147 Cov.: 32 AF XY: 0.0997 AC XY: 7423 AN XY: 74470

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0831

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.0767

Gnomad4 FIN AF: 0.0666

Gnomad4 NFE AF: 0.0495

Gnomad4 OTH AF: 0.0865

Alfa AF: 0.0601 Hom.: 958

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	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Benign	0.13	T
Polyphen		0.54	P
Vest4		0.14
MPC		0.31
ClinPred		0.042	T
GERP RS		4.8
Varity_R		0.15
gMVP		0.39

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

Other links and lift over

dbSNP: rs240768; hg19: chr6-100957344; COSMIC: COSV64972320;