rs201018893

Positions:

• chr9-100297931-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_014425.5(INVS):​c.3017-5T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 1,614,094 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (21 hom.)
• Consequence: INVS NM_014425.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9864
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.94

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 9-100297931-T-G is Benign according to our data. Variant chr9-100297931-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 260415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100297931-T-G is described in Lovd as [Benign]. Variant chr9-100297931-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00202 (307/152298) while in subpopulation SAS AF= 0.00994 (48/4830). AF 95% confidence interval is 0.0077. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.3017-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262457.7
INVS	NM_001318381.2	c.2729-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INVS	NM_001318382.2	c.2039-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
INVS	NR_134606.2	n.3166-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.3017-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014425.5	A2
INVS	ENST00000262456.6	c.2507-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		P4

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152180 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00276 AC: 695 AN: 251466 Hom.: 7 AF XY: 0.00338 AC XY: 459 AN XY: 135902

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00256 AC: 3738 AN: 1461796 Hom.: 21 Cov.: 31 AF XY: 0.00287 AC XY: 2084 AN XY: 727202

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152298 Hom.: 2 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74466

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00784

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00994

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.00170

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Infantile nephronophthisis Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 28, 2017	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.73		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs201018893; hg19: chr9-103060213;