chr6-5999014-A-C

Position:

• chr6-5999014-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016588.3(NRN1):​c.391T>G​(p.Ser131Ala) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRN1 NM_016588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0900

Genes affected

NRN1 (HGNC:17972): (neuritin 1) This gene encodes a member of the neuritin family, and is expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the adult. The expression of this gene can be induced by neural activity and neurotrophins. The encoded protein contains a consensus cleavage signal found in glycosylphoshatidylinositol (GPI)-anchored proteins. The encoded protein promotes neurite outgrowth and arborization, suggesting its role in promoting neuritogenesis. Overexpression of the encoded protein may be associated with astrocytoma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

NRN1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048127443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRN1	NM_016588.3	c.391T>G	p.Ser131Ala	missense_variant	3/3	ENST00000244766.7	NP_057672.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRN1	ENST00000244766.7	c.391T>G	p.Ser131Ala	missense_variant	3/3	1	NM_016588.3	ENSP00000244766.2
NRN1	ENST00000622188.4	c.469T>G	p.Ser157Ala	missense_variant	4/4	2		ENSP00000480483.1
NRN1	ENST00000616243.1	c.391T>G	p.Ser131Ala	missense_variant	4/4	4		ENSP00000484055.1
NRN1	ENST00000495850.1	n.474T>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Apr 07, 2023

The c.391T>G (p.S131A) alteration is located in exon 3 (coding exon 3) of the NRN1 gene. This alteration results from a T to G substitution at nucleotide position 391, causing the serine (S) at amino acid position 131 to be replaced by an alanine (A). 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	0.056
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.072	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.42	.;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.048	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.69	N;.;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.59	N;.;.
REVEL	Benign	0.045
Sift	Benign	0.76	T;.;.
Sift4G	Benign	0.84	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.12
MutPred		0.35		Loss of glycosylation at S131 (P = 0.0485);.;Loss of glycosylation at S131 (P = 0.0485);
MVP		0.068
MPC		0.59
ClinPred		0.064	T
GERP RS		0.50
Varity_R		0.045
gMVP		0.63

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: chr6-5999247;