9-100099331-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014425.5(INVS):c.-110T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 153,298 control chromosomes in the GnomAD database, including 3,521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3478 hom., cov: 31)
  • Exomes 𝑓: 0.26 (43 hom.)
• Consequence: INVS NM_014425.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.634

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 9-100099331-T-G is Benign according to our data. Variant chr9-100099331-T-G is described in ClinVar as [Benign]. Clinvar id is 364220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.-110T>G		5_prime_UTR_variant	1/17	ENST00000262457.7
INVS	NM_001318381.2	c.-486T>G		5_prime_UTR_variant	1/18
INVS	NM_001318382.2	c.-1099T>G		5_prime_UTR_variant	1/17
INVS	NR_134606.2	n.89T>G		non_coding_transcript_exon_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.-110T>G		5_prime_UTR_variant	1/17	1	NM_014425.5	A2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26656 AN: 151948 Hom.: 3477 Cov.: 31

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.238

Gnomad EAS AF: 0.642

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.215

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.180

GnomAD4 exome AF: 0.262 AC: 323 AN: 1232 Hom.: 43 Cov.: 0 AF XY: 0.261 AC XY: 221 AN XY: 846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.313

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.170

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.175 AC: 26666 AN: 152066 Hom.: 3478 Cov.: 31 AF XY: 0.184 AC XY: 13655 AN XY: 74348

Gnomad4 AFR AF: 0.0528

Gnomad4 AMR AF: 0.269

Gnomad4 ASJ AF: 0.238

Gnomad4 EAS AF: 0.643

Gnomad4 SAS AF: 0.321

Gnomad4 FIN AF: 0.215

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.182

Alfa AF: 0.182 Hom.: 5120

Bravo AF: 0.178

Asia WGS AF: 0.436 AC: 1509 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 634/2178=29.1% -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2016	- -

Kidney disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 01, 2019

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Infantile nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	13
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs7024375; hg19: chr9-102861613;