rs760013326

chr9-100300652-C-CA

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BS1_Supporting

The NM_014425.5(INVS):c.3182dup(p.Asn1061LysfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,613,004 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (2 hom.)
• Consequence: INVS NM_014425.5 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.78

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1170 codons.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00048 (73/152188) while in subpopulation AFR AF= 0.00128 (53/41538). AF 95% confidence interval is 0.001. There are 1 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.3182dup	p.Asn1061LysfsTer20	frameshift_variant	17/17	ENST00000262457.7
INVS	NM_001318381.2	c.2894dup	p.Asn965LysfsTer20	frameshift_variant	18/18
INVS	NM_001318382.2	c.2204dup	p.Asn735LysfsTer20	frameshift_variant	17/17
INVS	NR_134606.2	n.3331dup		non_coding_transcript_exon_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.3182dup	p.Asn1061LysfsTer20	frameshift_variant	17/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.2672dup	p.Asn891LysfsTer20	frameshift_variant	18/18	5		P4

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000128 AC: 32 AN: 250686 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135540

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.0000705 AC: 103 AN: 1460816 Hom.: 2 Cov.: 30 AF XY: 0.0000771 AC XY: 56 AN XY: 726774

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74412

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000240 Hom.: 0

Bravo AF: 0.000351

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 31, 2023

Variant summary: INVS c.3182dupA (p.Asn1061LysfsX20) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.00013 in 250686 control chromosomes. c.3182dupA has been reported in the literature in a patient with Bardet-Biedl syndrome and a patient with kidney and urinary tract abnormalities without evidence for causality (Nicolaou_2016 and Redin_2012). These reports do not provide unequivocal conclusions about association of the variant with Infantile Nephronophthisis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26489027, 22773737). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 15, 2018

- -

Infantile nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Apr 20, 2022

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs760013326; hg19: chr9-103062934;