chr6-5999032-A-G

Position:

• chr6-5999032-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_016588.3(NRN1):​c.373T>C​(p.Phe125Leu) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NRN1 NM_016588.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.665

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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043045044).
• BP6: Variant 6-5999032-A-G is Benign according to our data. Variant chr6-5999032-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2569427.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRN1	NM_016588.3	c.373T>C	p.Phe125Leu	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.373T>C	p.Phe125Leu	missense_variant	3/3	1	NM_016588.3	ENSP00000244766.2
NRN1	ENST00000622188.4	c.451T>C	p.Phe151Leu	missense_variant	4/4	2		ENSP00000480483.1
NRN1	ENST00000616243.1	c.373T>C	p.Phe125Leu	missense_variant	4/4	4		ENSP00000484055.1
NRN1	ENST00000495850.1	n.456T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.64
DEOGEN2	Benign	0.063	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.41	.;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.14	N;.;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	1.3	N;.;.
REVEL	Benign	0.021
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.081
MutPred		0.24		Gain of glycosylation at P123 (P = 0.0683);.;Gain of glycosylation at P123 (P = 0.0683);
MVP		0.043
MPC		0.83
ClinPred		0.062	T
GERP RS		0.41
Varity_R		0.039
gMVP		0.28

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: chr6-5999265;