12-107775516-C-G

Variant names:

• chr12-107775516-C-G
• rs781541284
• NM_203436.3:c.298C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203436.3(ASCL4):​c.298C>G​(p.Pro100Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P100T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ASCL4 NM_203436.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.58
• Publications: 0 publications found

Genes affected

ASCL4 (HGNC:24311): (achaete-scute family bHLH transcription factor 4) Basic helix-loop-helix transcription factors, such as ASCL4, are essential for the determination of cell fate and the development and differentiation of numerous tissues (Jonsson et al., 2004 [PubMed 15475265]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203436.3. 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
	ASCL4	NM_203436.3	MANE Select	c.298C>G	p.Pro100Ala	missense	Exon 1 of 1	NP_982260.3	Q6XD76

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL4	ENST00000342331.5	TSL:6 MANE Select	c.298C>G	p.Pro100Ala	missense	Exon 1 of 1	ENSP00000345420.5	Q6XD76

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000557 AC: 1 AN: 179616 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000692

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Vest4		0.84
MVP		0.78
MPC		1.3
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.69
Mutation Taster		=47/53	disease causing

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: rs781541284; hg19: chr12-108169293;