rs146370051

Variant names:

• chr10-72133059-T-C
• rs146370051
• NM_001198800.3:c.869A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001198800.3(ASCC1):​c.869A>G​(p.Asn290Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00201 in 1,613,978 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (3 hom.)
• Consequence: ASCC1 NM_001198800.3 missense, splice_region
• Scores: Splicing: ADA: 0.00006728
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: 0.926
• Publications: 12 publications found

Genes affected

ASCC1 (HGNC:24268): (activating signal cointegrator 1 complex subunit 1) This gene encodes a subunit of the activating signal cointegrator 1 (ASC-1) complex. The ASC-1 complex is a transcriptional coactivator that plays an important role in gene transactivation by multiple transcription factors including activating protein 1 (AP-1), nuclear factor kappa-B (NF-kB) and serum response factor (SRF). The encoded protein contains an N-terminal KH-type RNA-binding motif which is required for AP-1 transactivation by the ASC-1 complex. Mutations in this gene are associated with Barrett esophagus and esophageal adenocarcinoma. Alternatively spliced transcripts encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

ASCC1 Gene-Disease associations (from GenCC):

• spinal muscular atrophy with congenital bone fractures 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004810542).
• BP6: Variant 10-72133059-T-C is Benign according to our data. Variant chr10-72133059-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 31129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00128 (195/152296) while in subpopulation NFE AF = 0.00229 (156/68016). AF 95% confidence interval is 0.002. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001198800.3. 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
	ASCC1	NM_001198800.3	MANE Select	c.869A>G	p.Asn290Ser	missense splice_region	Exon 8 of 10	NP_001185729.1	Q8N9N2-2
	ASCC1	NM_001198799.3		c.953A>G	p.Asn318Ser	missense splice_region	Exon 9 of 13	NP_001185728.1	Q8N9N2-1
	ASCC1	NM_001369085.1		c.935A>G	p.Asn312Ser	missense splice_region	Exon 8 of 12	NP_001356014.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCC1	ENST00000672957.1	MANE Select	c.869A>G	p.Asn290Ser	missense splice_region	Exon 8 of 10	ENSP00000500935.1	Q8N9N2-2
	ASCC1	ENST00000342444.8	TSL:2	c.953A>G	p.Asn318Ser	missense splice_region	Exon 9 of 13	ENSP00000339404.4	Q8N9N2-1
	ASCC1	ENST00000394915.7	TSL:5	c.953A>G	p.Asn318Ser	missense splice_region	Exon 9 of 12	ENSP00000378373.3	Q8N9N2-1

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00117 AC: 294 AN: 251444 AF XY: 0.00131

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00186

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00209 AC: 3052 AN: 1461682 Hom.: 3 Cov.: 31 AF XY: 0.00205 AC XY: 1493 AN XY: 727146

African (AFR) AF: 0.000329 AC: 11 AN: 33474

American (AMR) AF: 0.000738 AC: 33 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00249 AC: 65 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86256

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53404

Middle Eastern (MID) AF: 0.00468 AC: 27 AN: 5768

European-Non Finnish (NFE) AF: 0.00248 AC: 2758 AN: 1111882

Other (OTH) AF: 0.00169 AC: 102 AN: 60374

GnomAD4 genome AF: 0.00128 AC: 195 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74488

African (AFR) AF: 0.000553 AC: 23 AN: 41554

American (AMR) AF: 0.000457 AC: 7 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00199 Hom.: 2

Bravo AF: 0.00129

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00327

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
1	-	-	BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMA (1)
-	-	1	not specified (1)
-	-	1	Spinal muscular atrophy with congenital bone fractures 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.82
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.71	N
PhyloP100		0.93
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.12
MVP		0.19
MPC		0.14
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.042
gMVP		0.22
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.020		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: rs146370051; hg19: chr10-73892817; COSMIC: COSV105161029;