1-176888072-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004319.3(ASTN1):c.3073G>C(p.Val1025Leu) variant causes a missense, splice region 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. 13/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASTN1 NM_004319.3 missense, splice_region
• Scores: Splicing: ADA: 0.01350
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31227475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASTN1	NM_004319.3	c.3073G>C	p.Val1025Leu	missense_variant, splice_region_variant	18/23	ENST00000361833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASTN1	ENST00000361833.7	c.3073G>C	p.Val1025Leu	missense_variant, splice_region_variant	18/23	1	NM_004319.3	P1
ASTN1	ENST00000367657.7	c.3073G>C	p.Val1025Leu	missense_variant, splice_region_variant	18/23	1
ASTN1	ENST00000424564.2	c.3073G>C	p.Val1025Leu	missense_variant, splice_region_variant	18/22	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 07, 2022

The c.3073G>C (p.V1025L) alteration is located in exon 18 (coding exon 18) of the ASTN1 gene. This alteration results from a G to C substitution at nucleotide position 3073, causing the valine (V) at amino acid position 1025 to be replaced by a leucine (L). 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	-0.072	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;.
Eigen	Benign	-0.099
Eigen_PC	Benign	0.049
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.0050	B;B;.
Vest4		0.41
MutPred		0.22		Gain of glycosylation at P1024 (P = 0.093);Gain of glycosylation at P1024 (P = 0.093);Gain of glycosylation at P1024 (P = 0.093);
MVP		0.68
MPC		0.23
ClinPred		0.58	D
GERP RS		5.8
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.014
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs1204954294; hg19: chr1-176857208;