Genetic Variant VIP:p.Thr135Ile (chr6-152756202-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003381.4(VIP):c.404C>T(p.Thr135Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,459,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

VIP
NM_003381.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.59

Variant links:

Genes affected

VIP (HGNC:12693): (vasoactive intestinal peptide) The protein encoded by this gene belongs to the glucagon family. It stimulates myocardial contractility, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2014]

VIP links:

LINC02840 (HGNC:54374): (long intergenic non-protein coding RNA 2840)

LINC02840 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VIP	NM_003381.4 link	c.404C>T	p.Thr135Ile	missense_variant	Exon 5 of 7	ENST00000367244.8	NP_003372.1	P01282-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VIP	ENST00000367244.8 link	c.404C>T	p.Thr135Ile	missense_variant	Exon 5 of 7	1	NM_003381.4	ENSP00000356213.3	P01282-1
VIP	ENST00000367243.7 link	c.401C>T	p.Thr134Ile	missense_variant	Exon 5 of 7	1		ENSP00000356212.3	P01282-2
VIP	ENST00000431366.1 link	c.251C>T	p.Thr84Ile	missense_variant	Exon 3 of 5	3		ENSP00000410356.1	H0Y763
LINC02840	ENST00000666093.1 link	n.3119G>A		non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

250392

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459800

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404C>T (p.T135I) alteration is located in exon 5 (coding exon 4) of the VIP gene. This alteration results from a C to T substitution at nucleotide position 404, causing the threonine (T) at amino acid position 135 to be replaced by an isoleucine (I). 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

0.98

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.97

D;D

Vest4

0.41

MutPred

0.80

Loss of phosphorylation at T131 (P = 0.079);.;

MVP

0.099

MPC

0.58

ClinPred

0.84

GERP RS

5.3

Varity_R

0.56

gMVP

0.45

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over