12-102958371-G-T

Variant names:

• chr12-102958371-G-T
• rs1046623355
• NM_004316.4:c.127G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004316.4(ASCL1):​c.127G>T​(p.Ala43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000773 in 1,293,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A43T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: ASCL1 NM_004316.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.37
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.106775016).

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.127G>T	p.Ala43Ser	missense	Exon 1 of 2	NP_004307.2	P50553
	PAH	NM_001354304.2		c.-272C>A		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.127G>T	p.Ala43Ser	missense	Exon 1 of 2	ENSP00000266744.3	P50553
	PAH	ENST00000547319.1	TSL:4	n.40C>A		non_coding_transcript_exon	Exon 1 of 3
	PAH	ENST00000551337.5	TSL:3	c.-272C>A		upstream_gene	N/A	ENSP00000447620.1	F8W0A0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.73e-7 AC: 1 AN: 1293052 Hom.: 0 Cov.: 29 AF XY: 0.00000157 AC XY: 1 AN XY: 636866

African (AFR) AF: 0.00 AC: 0 AN: 25206

American (AMR) AF: 0.00 AC: 0 AN: 18746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21508

East Asian (EAS) AF: 0.00 AC: 0 AN: 28328

South Asian (SAS) AF: 0.00 AC: 0 AN: 65538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3904

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035792

Other (OTH) AF: 0.0000189 AC: 1 AN: 52982

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000529 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.30	N
REVEL	Benign	0.10
Sift	Uncertain	0.016	D
Sift4G	Benign	0.69	T
Polyphen		0.015	B
Vest4		0.25
MutPred		0.32		Gain of glycosylation at A43 (P = 0.0017)
MVP		0.42
MPC		0.93
ClinPred		0.075	T
GERP RS		2.3
PromoterAI		-0.030	Neutral
Varity_R		0.097
gMVP		0.41
Mutation Taster		=94/6	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: rs1046623355; hg19: chr12-103352149;