6-100864129-T-G

Variant names:

• chr6-100864129-T-G
• rs757903799
• NM_006828.4:c.176A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E59G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ASCC3 NM_006828.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.31
• Publications: 3 publications found

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

ACMG classification

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 VariationId is 522895.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006828.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCC3	NM_006828.4	MANE Select	c.176A>C	p.Glu59Ala	missense	Exon 3 of 42	NP_006819.2	Q8N3C0-1
	ASCC3	NM_001284271.2		c.176A>C	p.Glu59Ala	missense	Exon 3 of 13	NP_001271200.1	Q8N3C0-4
	ASCC3	NM_022091.5		c.176A>C	p.Glu59Ala	missense	Exon 3 of 4	NP_071374.1	Q8N3C0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCC3	ENST00000369162.7	TSL:5 MANE Select	c.176A>C	p.Glu59Ala	missense	Exon 3 of 42	ENSP00000358159.2	Q8N3C0-1
	ASCC3	ENST00000522650.5	TSL:1	c.176A>C	p.Glu59Ala	missense	Exon 3 of 13	ENSP00000430769.1	Q8N3C0-4
	ASCC3	ENST00000369143.2	TSL:1	c.176A>C	p.Glu59Ala	missense	Exon 3 of 4	ENSP00000358139.2	Q8N3C0-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453602 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723788

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51628

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106426

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.10
Sift	Benign	0.20	T
Sift4G	Benign	0.65	T
Polyphen		0.043	B
Vest4		0.27
MutPred		0.41		Gain of MoRF binding (P = 0.0303)
MVP		0.38
MPC		0.27
ClinPred		0.78	D
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

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

Other links and lift over

dbSNP: rs757903799; hg19: chr6-101312005;