1-176894639-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004319.3(ASTN1):c.2863C>G(p.Pro955Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,860 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (1 hom.)
• Consequence: ASTN1 NM_004319.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.63

Genes affected

ASTN1 (HGNC:773): (astrotactin 1) Astrotactin is a neuronal adhesion molecule required for glial-guided migration of young postmitotic neuroblasts in cortical regions of developing brain, including cerebrum, hippocampus, cerebellum, and olfactory bulb (Fink et al., 1995).[supplied by OMIM, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1394907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASTN1	NM_004319.3	c.2863C>G	p.Pro955Ala	missense_variant	17/23	ENST00000361833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASTN1	ENST00000361833.7	c.2863C>G	p.Pro955Ala	missense_variant	17/23	1	NM_004319.3	P1
ASTN1	ENST00000367657.7	c.2863C>G	p.Pro955Ala	missense_variant	17/23	1
ASTN1	ENST00000424564.2	c.2863C>G	p.Pro955Ala	missense_variant	17/22	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461860 Hom.: 1 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.2863C>G (p.P955A) alteration is located in exon 17 (coding exon 17) of the ASTN1 gene. This alteration results from a C to G substitution at nucleotide position 2863, causing the proline (P) at amino acid position 955 to be replaced by an alanine (A). 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
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;D;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Benign	0.065
Sift	Benign	0.073	T;T;T
Sift4G	Uncertain	0.031	D;D;D
Polyphen		0.058	B;B;.
Vest4		0.15
MutPred		0.16		Loss of disorder (P = 0.0772);Loss of disorder (P = 0.0772);Loss of disorder (P = 0.0772);
MVP		0.10
MPC		0.23
ClinPred		0.59	D
GERP RS		5.3
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-176863775;