6-24145821-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_080723.5(NRSN1):c.463A>C(p.Lys155Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRSN1 NM_080723.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

Genes affected

NRSN1 (HGNC:17881): (neurensin 1) Predicted to be involved in nervous system development. Predicted to be located in cytoplasmic vesicle and growth cone. Predicted to be active in neuron projection; neuronal cell body; and transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34428596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRSN1	NM_080723.5	c.463A>C	p.Lys155Gln	missense_variant	4/4	ENST00000378491.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRSN1	ENST00000378491.9	c.463A>C	p.Lys155Gln	missense_variant	4/4	1	NM_080723.5	P1
NRSN1	ENST00000378478.5	c.463A>C	p.Lys155Gln	missense_variant	4/4	1		P1
NRSN1	ENST00000378477.2	c.463A>C	p.Lys155Gln	missense_variant	4/4	1
NRSN1	ENST00000468195.2	n.257-8950A>C		intron_variant, non_coding_transcript_variant		5

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.463A>C (p.K155Q) alteration is located in exon 4 (coding exon 2) of the NRSN1 gene. This alteration results from a A to C substitution at nucleotide position 463, causing the lysine (K) at amino acid position 155 to be replaced by a glutamine (Q). 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.039	T;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.29	N;.;N
REVEL	Benign	0.17
Sift	Benign	0.039	D;.;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.95	P;P;.
Vest4		0.19
MutPred		0.47		Loss of methylation at K155 (P = 0.009);Loss of methylation at K155 (P = 0.009);Loss of methylation at K155 (P = 0.009);
MVP		0.68
MPC		0.33
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.21
gMVP		0.70

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-24146049;