1-176884476-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_004319.3(ASTN1):c.3089C>T(p.Thr1030Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,612,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: ASTN1 NM_004319.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.32

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025105715).
• BP6: Variant 1-176884476-G-A is Benign according to our data. Variant chr1-176884476-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2569888.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASTN1	NM_004319.3	c.3089C>T	p.Thr1030Met	missense_variant	19/23	ENST00000361833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASTN1	ENST00000361833.7	c.3089C>T	p.Thr1030Met	missense_variant	19/23	1	NM_004319.3	P1
ASTN1	ENST00000367657.7	c.3089C>T	p.Thr1030Met	missense_variant	19/23	1
ASTN1	ENST00000424564.2	c.3089C>T	p.Thr1030Met	missense_variant	19/22	1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 251150 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135712

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000100 AC: 146 AN: 1460594 Hom.: 0 Cov.: 30 AF XY: 0.0000950 AC XY: 69 AN XY: 726376

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000756

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74482

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000998 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.3089C>T (p.T1030M) alteration is located in exon 19 (coding exon 19) of the ASTN1 gene. This alteration results from a C to T substitution at nucleotide position 3089, causing the threonine (T) at amino acid position 1030 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2023

ASTN1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.041	T;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.90	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.73	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.33
MVP		0.16
MPC		0.25
ClinPred		0.022	T
GERP RS		1.8
gMVP		0.33

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

Other links and lift over

dbSNP: rs143440206; hg19: chr1-176853612; COSMIC: COSV62501149;