NM_004319.3:c.3404G>A

Variant names:

• chr1-176876596-C-T
• NM_004319.3:c.3404G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004319.3(ASTN1):​c.3404G>A​(p.Arg1135Lys) variant causes a missense 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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASTN1 NM_004319.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.78
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15840626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASTN1	NM_004319.3	c.3404G>A	p.Arg1135Lys	missense_variant	Exon 21 of 23	ENST00000361833.7	NP_004310.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASTN1	ENST00000361833.7	c.3404G>A	p.Arg1135Lys	missense_variant	Exon 21 of 23	1	NM_004319.3	ENSP00000354536.2
ASTN1	ENST00000367657.7	c.3404G>A	p.Arg1135Lys	missense_variant	Exon 21 of 23	1		ENSP00000356629.3
ASTN1	ENST00000424564.2	c.3404G>A	p.Arg1135Lys	missense_variant	Exon 21 of 22	1		ENSP00000395041.2
ASTN1	ENST00000850957.1	c.3428G>A	p.Arg1143Lys	missense_variant	Exon 21 of 23			ENSP00000521041.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3404G>A (p.R1135K) alteration is located in exon 21 (coding exon 21) of the ASTN1 gene. This alteration results from a G to A substitution at nucleotide position 3404, causing the arginine (R) at amino acid position 1135 to be replaced by a lysine (K). 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	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.067
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.38	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.35
MutPred		0.22		Gain of ubiquitination at R1135 (P = 0.03);Gain of ubiquitination at R1135 (P = 0.03);Gain of ubiquitination at R1135 (P = 0.03);
MVP		0.17
MPC		0.25
ClinPred		0.74	D
GERP RS		4.3
gMVP		0.52
Mutation Taster		=81/19	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

hg19: chr1-176845732; COSMIC: COSV62503813;