Genetic Variant ASCC1:p.Tyr348* (chr10-72097364-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_ModeratePM2

The NM_001198800.3(ASCC1):c.1044C>A(p.Tyr348*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y348Y) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ASCC1
NM_001198800.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.42

Publications

0 publications found

Variant links:

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)

ASCC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0279 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASCC1	NM_001198800.3	MANE Select	c.1044C>A	p.Tyr348*	stop_gained	Exon 10 of 10	NP_001185729.1	Q8N9N2-2
ASCC1	NM_001198798.2		c.1044C>A	p.Tyr348*	stop_gained	Exon 10 of 10	NP_001185727.1	Q8N9N2-2
ASCC1	NM_001369093.1		c.1044C>A	p.Tyr348*	stop_gained	Exon 10 of 10	NP_001356022.1	Q8N9N2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ASCC1	ENST00000672957.1	MANE Select	c.1044C>A	p.Tyr348*	stop_gained	Exon 10 of 10	ENSP00000500935.1	Q8N9N2-2
ASCC1	ENST00000902262.1		c.1128C>A	p.Tyr376*	stop_gained	Exon 11 of 11	ENSP00000572321.1
ASCC1	ENST00000672774.1		c.1104C>A	p.Tyr368*	stop_gained	Exon 11 of 11	ENSP00000500488.1	A0A5F9ZHP1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461070

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726866

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111360

Other (OTH)

AF:

0.00

AC:

AN:

60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Pathogenic

(source)

DANN

Benign

0.97

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.11

PhyloP100

-1.4

Vest4

0.29

GERP RS

-6.7

Mutation Taster

=33/167

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over