chr6-5999071-C-T

Variant names:

• chr6-5999071-C-T
• NM_016588.3:c.334G>A

Variant summary

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

The NM_016588.3(NRN1):​c.334G>A​(p.Gly112Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRN1 NM_016588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

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]

ENSG00000300014 (HGNC:):

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=0.09869638).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016588.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRN1	NM_016588.3	MANE Select	c.334G>A	p.Gly112Ser	missense	Exon 3 of 3	NP_057672.1	Q9NPD7
	NRN1	NM_001278711.2		c.412G>A	p.Gly138Ser	missense	Exon 4 of 4	NP_001265640.1	A0A087WWT2
	NRN1	NM_001278710.2		c.334G>A	p.Gly112Ser	missense	Exon 4 of 4	NP_001265639.1	Q9NPD7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRN1	ENST00000244766.7	TSL:1 MANE Select	c.334G>A	p.Gly112Ser	missense	Exon 3 of 3	ENSP00000244766.2	Q9NPD7
	NRN1	ENST00000622188.4	TSL:2	c.412G>A	p.Gly138Ser	missense	Exon 4 of 4	ENSP00000480483.1	A0A087WWT2
	NRN1	ENST00000616243.1	TSL:4	c.334G>A	p.Gly112Ser	missense	Exon 4 of 4	ENSP00000484055.1	Q9NPD7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.060	N
PhyloP100		4.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.063
Sift	Benign	0.68	T
Sift4G	Benign	0.81	T
Polyphen		0.017	B
Vest4		0.31
MutPred		0.21		Gain of disorder (P = 0.0844)
MVP		0.043
MPC		0.71
ClinPred		0.73	D
GERP RS		2.6
Varity_R		0.054
gMVP		0.70
Mutation Taster		=71/29	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: chr6-5999304; COSMIC: COSV55205498;