Genetic Variant ASCL1:p.Met7Ile (chr12-102958265-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004316.4(ASCL1):c.21G>C(p.Met7Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000159 in 1,322,534 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 1 hom. )

Consequence

ASCL1
NM_004316.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.91

Variant links:

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]

ASCL1 links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASCL1	NM_004316.4 link	c.21G>C	p.Met7Ile	missense_variant	Exon 1 of 2	ENST00000266744.4	NP_004307.2	P50553
PAH	NM_001354304.2 link	c.-166C>G		5_prime_UTR_variant	Exon 1 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ASCL1	ENST00000266744.4 link	c.21G>C	p.Met7Ile	missense_variant	Exon 1 of 2	1	NM_004316.4	ENSP00000266744.3	P50553
PAH	ENST00000551337.5 link	c.-166C>G		5_prime_UTR_variant	Exon 1 of 5	3		ENSP00000447620.1	F8W0A0
PAH	ENST00000547319.1 link	n.146C>G		non_coding_transcript_exon_variant	Exon 1 of 3	4
PAH	ENST00000635500.1 link	n.-43C>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000612

AC:

AN:

81732

Hom.:

AF XY:

0.0000855

AC XY:

AN XY:

46774

show subpopulations

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 SAS exome

AF:

0.000303

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1322534

Hom.:

Cov.:

AF XY:

0.0000230

AC XY:

AN XY:

651632

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000279

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000183

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000682

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.21G>C (p.M7I) alteration is located in exon 1 (coding exon 1) of the ASCL1 gene. This alteration results from a G to C substitution at nucleotide position 21, causing the methionine (M) at amino acid position 7 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.83

MetaRNN

Uncertain

0.50

MetaSVM

Pathogenic

0.84

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.46

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.92

Vest4

0.55

MutPred

0.22

Gain of catalytic residue at A12 (P = 0.0031);

MVP

0.93

MPC

1.1

ClinPred

0.35

GERP RS

4.1

Varity_R

0.94

gMVP

0.67

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over