NM_004319.3:c.3283A>C

Variant names:

• chr1-176882938-T-G
• rs151246825
• NM_004319.3:c.3283A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004319.3(ASTN1):​c.3283A>C​(p.Met1095Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,614,114 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (17 hom.)
• Consequence: ASTN1 NM_004319.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 7.60
• Publications: 3 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007880479).
• BP6: Variant 1-176882938-T-G is Benign according to our data. Variant chr1-176882938-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438600.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004319.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTN1	NM_004319.3	MANE Select	c.3283A>C	p.Met1095Leu	missense	Exon 20 of 23	NP_004310.1
	ASTN1	NM_001364856.2		c.3307A>C	p.Met1103Leu	missense	Exon 20 of 23	NP_001351785.1
	ASTN1	NM_001286164.2		c.3283A>C	p.Met1095Leu	missense	Exon 20 of 23	NP_001273093.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASTN1	ENST00000361833.7	TSL:1 MANE Select	c.3283A>C	p.Met1095Leu	missense	Exon 20 of 23	ENSP00000354536.2
	ASTN1	ENST00000367657.7	TSL:1	c.3283A>C	p.Met1095Leu	missense	Exon 20 of 23	ENSP00000356629.3
	ASTN1	ENST00000424564.2	TSL:1	c.3283A>C	p.Met1095Leu	missense	Exon 20 of 22	ENSP00000395041.2

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152116 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00747

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00348 AC: 876 AN: 251406 AF XY: 0.00381

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00396

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00380 AC: 5549 AN: 1461880 Hom.: 17 Cov.: 31 AF XY: 0.00392 AC XY: 2850 AN XY: 727242

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00976 AC: 255 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00693 AC: 598 AN: 86256

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53420

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00389 AC: 4322 AN: 1112000

Other (OTH) AF: 0.00364 AC: 220 AN: 60396

GnomAD4 genome AF: 0.00273 AC: 416 AN: 152234 Hom.: 4 Cov.: 31 AF XY: 0.00249 AC XY: 185 AN XY: 74438

African (AFR) AF: 0.000602 AC: 25 AN: 41536

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00748 AC: 36 AN: 4814

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68026

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00249

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00342 AC: 415

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00439

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Abnormal corpus callosum morphology (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.89	T
PhyloP100		7.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.24
Sift	Benign	0.088	T
Sift4G	Benign	0.46	T
Polyphen		0.26	B
Vest4		0.63
MutPred		0.12		Loss of methylation at K1090 (P = 0.0888)
MVP		0.37
MPC		0.55
ClinPred		0.039	T
GERP RS		5.7
gMVP		0.48
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151246825; hg19: chr1-176852074; COSMIC: COSV99054523;