12-102958048-T-C

Variant names:

• chr12-102958048-T-C
• rs9782
• NM_004316.4:c.-197T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004316.4(ASCL1):​c.-197T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 407,558 control chromosomes in the GnomAD database, including 22,585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10284 hom., cov: 32)
  • Exomes 𝑓: 0.30 (12301 hom.)
• Consequence: ASCL1 NM_004316.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.365
• Publications: 22 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), G2P, ClinGen, Myriad Women’s Health
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-102958048-T-C is Benign according to our data. Variant chr12-102958048-T-C is described in ClinVar as Benign. ClinVar VariationId is 1229581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4	c.-197T>C		5_prime_UTR_variant	Exon 1 of 2	ENST00000266744.4	NP_004307.2
PAH	NM_001354304.2	c.-96+147A>G		intron_variant	Intron 1 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASCL1	ENST00000266744.4	c.-197T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3
PAH	ENST00000551337.5	c.-96+147A>G		intron_variant	Intron 1 of 4	3		ENSP00000447620.1
PAH	ENST00000547319.1	n.216+147A>G		intron_variant	Intron 1 of 2	4
PAH	ENST00000635500.1	n.28+147A>G		intron_variant	Intron 1 of 2	3

Frequencies

GnomAD3 genomes AF: 0.355 AC: 53834 AN: 151796 Hom.: 10275 Cov.: 32

Gnomad AFR AF: 0.501

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.345

GnomAD4 exome AF: 0.301 AC: 76964 AN: 255646 Hom.: 12301 Cov.: 4 AF XY: 0.300 AC XY: 38962 AN XY: 130024

African (AFR) AF: 0.509 AC: 3517 AN: 6910

American (AMR) AF: 0.267 AC: 1870 AN: 6994

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 2943 AN: 8776

East Asian (EAS) AF: 0.104 AC: 2258 AN: 21684

South Asian (SAS) AF: 0.197 AC: 793 AN: 4018

European-Finnish (FIN) AF: 0.291 AC: 6075 AN: 20908

Middle Eastern (MID) AF: 0.404 AC: 515 AN: 1274

European-Non Finnish (NFE) AF: 0.319 AC: 53899 AN: 168754

Other (OTH) AF: 0.312 AC: 5094 AN: 16328

GnomAD4 genome AF: 0.355 AC: 53870 AN: 151912 Hom.: 10284 Cov.: 32 AF XY: 0.349 AC XY: 25912 AN XY: 74274

African (AFR) AF: 0.501 AC: 20756 AN: 41420

American (AMR) AF: 0.278 AC: 4254 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1143 AN: 3472

East Asian (EAS) AF: 0.136 AC: 700 AN: 5140

South Asian (SAS) AF: 0.205 AC: 990 AN: 4818

European-Finnish (FIN) AF: 0.304 AC: 3213 AN: 10578

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21669 AN: 67876

Other (OTH) AF: 0.340 AC: 717 AN: 2110

Alfa AF: 0.327 Hom.: 35582

Bravo AF: 0.361

Asia WGS AF: 0.201 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	13
DANN	Benign	0.68
PhyloP100		0.36
PromoterAI		-0.14	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs9782; hg19: chr12-103351826;