NM_203436.3:c.473C>T

Variant names:

• chr12-107775691-C-T
• rs375790903
• NM_203436.3:c.473C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203436.3(ASCL4):​c.473C>T​(p.Ser158Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,470,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: ASCL4 NM_203436.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.39
• Publications: 1 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_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=0.018407524).

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.473C>T	p.Ser158Phe	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.473C>T	p.Ser158Phe	missense	Exon 1 of 1	ENSP00000345420.5	Q6XD76

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 11 AN: 103502 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00563

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000185

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.0000956 AC: 126 AN: 1318128 Hom.: 0 Cov.: 30 AF XY: 0.000115 AC XY: 74 AN XY: 644734

African (AFR) AF: 0.0000379 AC: 1 AN: 26360

American (AMR) AF: 0.00 AC: 0 AN: 25914

Ashkenazi Jewish (ASJ) AF: 0.00292 AC: 55 AN: 18850

East Asian (EAS) AF: 0.00 AC: 0 AN: 34010

South Asian (SAS) AF: 0.00 AC: 0 AN: 66150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34946

Middle Eastern (MID) AF: 0.000234 AC: 1 AN: 4278

European-Non Finnish (NFE) AF: 0.0000541 AC: 57 AN: 1053174

Other (OTH) AF: 0.000220 AC: 12 AN: 54446

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74380

African (AFR) AF: 0.0000482 AC: 2 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000252 AC: 2

ExAC AF: 0.000151 AC: 17

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.018	T
MetaSVM	Pathogenic	0.83	D
PhyloP100		3.4
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Vest4		0.32
MVP		0.67
MPC		0.48
ClinPred		0.31	T
GERP RS		4.6
gMVP		0.46
Mutation Taster		=95/5	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: rs375790903; hg19: chr12-108169468;