GeneBe

rs1554728033

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014425.5(INVS):​c.1571+2dupT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 7.0e-7 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

INVS
NM_014425.5 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.70

Publications

0 publications found
Variant links:
Genes affected
INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]
INVS Gene-Disease associations (from GenCC):
  • nephronophthisis 2
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • Senior-Loken syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
INVSNM_014425.5 linkc.1571+2dupT splice_region_variant, intron_variant Intron 11 of 16 ENST00000262457.7 NP_055240.2 Q9Y283-1A0A024R153
INVSNM_001318381.2 linkc.1283+2dupT splice_region_variant, intron_variant Intron 12 of 17 NP_001305310.1 Q2M1I4
INVSNM_001318382.2 linkc.593+2dupT splice_region_variant, intron_variant Intron 11 of 16 NP_001305311.1
INVSNR_134606.2 linkn.1769+2dupT splice_region_variant, intron_variant Intron 11 of 16

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
INVSENST00000262457.7 linkc.1571+1_1571+2insT splice_donor_variant, intron_variant Intron 11 of 16 1 NM_014425.5 ENSP00000262457.2 Q9Y283-1
INVSENST00000262456.6 linkc.1571+1_1571+2insT splice_donor_variant, intron_variant Intron 11 of 17 5 ENSP00000262456.2 Q9Y283-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
7.04e-7
AC:
1
AN:
1421120
Hom.:
0
Cov.:
27
AF XY:
0.00
AC XY:
0
AN XY:
709162
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
32552
American (AMR)
AF:
0.00
AC:
0
AN:
44584
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25856
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39472
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85376
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53264
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5684
European-Non Finnish (NFE)
AF:
9.30e-7
AC:
1
AN:
1075340
Other (OTH)
AF:
0.00
AC:
0
AN:
58992
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Nephronophthisis Uncertain:1
Oct 08, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change falls in intron 11 of the INVS gene. It does not directly change the encoded amino acid sequence of the INVS protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with INVS-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 531626). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
7.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.96
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1554728033; hg19: chr9-103027211; API