5-65762960-T-A

Position:

• chr5-65762960-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020726.5(NLN):​c.302T>A​(p.Val101Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NLN NM_020726.5 missense, splice_region
• Scores: Splicing: ADA: 0.7346
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

Genes affected

NLN (HGNC:16058): (neurolysin) This gene encodes a member of the metallopeptidase M3 protein family that cleaves neurotensin at the Pro10-Tyr11 bond, leading to the formation of neurotensin(1-10) and neurotensin(11-13). The encoded protein is likely involved in the termination of the neurotensinergic signal in the central nervous system and in the gastrointestinal tract.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NLN	NM_020726.5	c.302T>A	p.Val101Glu	missense_variant, splice_region_variant	3/13	ENST00000380985.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NLN	ENST00000380985.10	c.302T>A	p.Val101Glu	missense_variant, splice_region_variant	3/13	1	NM_020726.5	P1
NLN	ENST00000506539.5	n.418T>A		splice_region_variant, non_coding_transcript_exon_variant	3/9	1
NLN	ENST00000502464.5	c.-11T>A		splice_region_variant, 5_prime_UTR_variant	2/12	5
NLN	ENST00000514991.5	c.*261T>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	4/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 03, 2022

The c.302T>A (p.V101E) alteration is located in exon 3 (coding exon 3) of the NLN gene. This alteration results from a T to A substitution at nucleotide position 302, causing the valine (V) at amino acid position 101 to be replaced by a glutamic acid (E). 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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.039	D
Sift4G	Benign	0.18	T
Polyphen		0.98	D
Vest4		0.74
MutPred		0.65		Loss of catalytic residue at V101 (P = 0.0835);
MVP		0.70
MPC		0.24
ClinPred		0.96	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.010		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: chr5-65058787;