chr6-152756135-A-T

Variant names:

• chr6-152756135-A-T
• rs1306272102
• NM_003381.4:c.337A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_194435.3(VIP):​c.336-2A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: VIP NM_194435.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.0009247
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.2529412 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of -3, new splice context is: cttttcctcatgttccttAGctg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194435.3. 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
	VIP	NM_003381.4	MANE Select	c.337A>T	p.Ser113Cys	missense splice_region	Exon 5 of 7	NP_003372.1	P01282-1
	VIP	NM_194435.3		c.336-2A>T		splice_acceptor intron	N/A	NP_919416.1	P01282-2
	LINC02840	NR_183504.1		n.3135T>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VIP	ENST00000367244.8	TSL:1 MANE Select	c.337A>T	p.Ser113Cys	missense splice_region	Exon 5 of 7	ENSP00000356213.3	P01282-1
	VIP	ENST00000367243.7	TSL:1	c.336-2A>T		splice_acceptor intron	N/A	ENSP00000356212.3	P01282-2
	VIP	ENST00000897584.1		c.337A>T	p.Ser113Cys	missense splice_region	Exon 5 of 7	ENSP00000567643.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000450 AC: 1 AN: 222202 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000955

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1406298 Hom.: 0 Cov.: 30 AF XY: 0.00000287 AC XY: 2 AN XY: 697476

African (AFR) AF: 0.00 AC: 0 AN: 30964

American (AMR) AF: 0.00 AC: 0 AN: 38034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23998

East Asian (EAS) AF: 0.00 AC: 0 AN: 38036

South Asian (SAS) AF: 0.00 AC: 0 AN: 74014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1086364

Other (OTH) AF: 0.00 AC: 0 AN: 57758

GnomAD4 genome Cov.: 32

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	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
DANN	Benign	0.89
Eigen	Benign	-0.045
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.089	D
PhyloP100		2.0
ClinPred		0.91	D
GERP RS		3.7
Varity_R		0.13
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00092
dbscSNV1_RF	Benign	0.0080
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

dbSNP: rs1306272102; hg19: chr6-153077270;