NM_004316.4:c.4G>A

Variant names:

• chr12-102958248-G-A
• rs1339147930
• NM_004316.4:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004316.4(ASCL1):​c.4G>A​(p.Glu2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASCL1 NM_004316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02
• Publications: 5 publications found

Genes affected

ASCL1 (HGNC:738): (achaete-scute family bHLH transcription factor 1) This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31910872).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004316.4. 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
	ASCL1	NM_004316.4	MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-149C>T		5_prime_UTR	Exon 1 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASCL1	ENST00000266744.4	TSL:1 MANE Select	c.4G>A	p.Glu2Lys	missense	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000551337.5	TSL:3	c.-149C>T		5_prime_UTR	Exon 1 of 5	ENSP00000447620.1	F8W0A0
	PAH	ENST00000547319.1	TSL:4	n.163C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 80556 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1318182 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 649370

African (AFR) AF: 0.00 AC: 0 AN: 26782

American (AMR) AF: 0.00 AC: 0 AN: 25558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23336

East Asian (EAS) AF: 0.00 AC: 0 AN: 28234

South Asian (SAS) AF: 0.00 AC: 0 AN: 70900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4352

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047204

Other (OTH) AF: 0.00 AC: 0 AN: 54520

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.088
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.044	D
Polyphen		0.012	B
Vest4		0.25
MutPred		0.26		Gain of MoRF binding (P = 0)
MVP		0.89
MPC		1.1
ClinPred		0.59	D
GERP RS		4.1
PromoterAI		0.0012	Neutral
Varity_R		0.38
gMVP		0.51
Mutation Taster		=87/13	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: rs1339147930; hg19: chr12-103352026;