NM_004319.3:c.3873C>A

Variant names:

• chr1-176864296-G-T
• rs971531077
• NM_004319.3:c.3873C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004319.3(ASTN1):​c.3873C>A​(p.Ser1291Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: ASTN1 NM_004319.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058986545).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTN1	NM_004319.3	c.3873C>A	p.Ser1291Arg	missense_variant	Exon 23 of 23	ENST00000361833.7	NP_004310.1
ASTN1	NM_001364856.2	c.3897C>A	p.Ser1299Arg	missense_variant	Exon 23 of 23		NP_001351785.1
ASTN1	NM_001286164.2	c.3647+4548C>A		intron_variant	Intron 22 of 22		NP_001273093.1
ASTN1	XM_017001341.3	c.3671+4548C>A		intron_variant	Intron 22 of 22		XP_016856830.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASTN1	ENST00000361833.7	c.3873C>A	p.Ser1291Arg	missense_variant	Exon 23 of 23	1	NM_004319.3	ENSP00000354536.2
ASTN1	ENST00000367657.7	c.3647+4548C>A		intron_variant	Intron 22 of 22	1		ENSP00000356629.3
ASTN1	ENST00000850957.1	c.3897C>A	p.Ser1299Arg	missense_variant	Exon 23 of 23			ENSP00000521041.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 251044 AF XY: 0.0000221

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461716 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727176

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111980

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3873C>A (p.S1291R) alteration is located in exon 23 (coding exon 23) of the ASTN1 gene. This alteration results from a C to A substitution at nucleotide position 3873, causing the serine (S) at amino acid position 1291 to be replaced by an arginine (R). 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	-0.32	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.059
Sift	Benign	0.084	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.070
MutPred		0.15		Loss of glycosylation at S1291 (P = 0.0342);
MVP		0.043
MPC		0.26
ClinPred		0.18	T
GERP RS		3.7
gMVP		0.38
Mutation Taster		=83/17	polymorphism

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: rs971531077; hg19: chr1-176833432;