chr1-176882938-T-G

Position:

• chr1-176882938-T-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 438600.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ASTN1	NM_004319.3	c.3283A>C	p.Met1095Leu	missense_variant	20/23	ENST00000361833.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ASTN1	ENST00000361833.7	c.3283A>C	p.Met1095Leu	missense_variant	20/23	1	NM_004319.3	P1
ASTN1	ENST00000367657.7	c.3283A>C	p.Met1095Leu	missense_variant	20/23	1
ASTN1	ENST00000424564.2	c.3283A>C	p.Met1095Leu	missense_variant	20/22	1

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

GnomAD3 exomes AF: 0.00348 AC: 876 AN: 251406 Hom.: 5 AF XY: 0.00381 AC XY: 517 AN XY: 135868

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 SAS exome AF: 0.00741

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

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.00976

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00693

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00389

Gnomad4 OTH exome AF: 0.00364

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

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00748

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00395

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00375 Hom.: 0

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	ASTN1: BS2 -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Abnormal corpus callosum morphology Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Sep 01, 2017

this variant was indentified in an individual with malformations of cortical development -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0079	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.74	N;N;N
REVEL	Benign	0.24
Sift	Benign	0.088	T;T;T
Sift4G	Benign	0.46	T;T;T
Polyphen		0.26	B;B;.
Vest4		0.63
MutPred		0.12		Loss of methylation at K1090 (P = 0.0888);Loss of methylation at K1090 (P = 0.0888);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs151246825; hg19: chr1-176852074; COSMIC: COSV99054523;