9-100297194-A-G

Variant names:

• chr9-100297194-A-G
• rs7864494
• NM_014425.5:c.3016+48A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014425.5(INVS):​c.3016+48A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,399,296 control chromosomes in the GnomAD database, including 285,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34892 hom., cov: 32)
  • Exomes 𝑓: 0.63 (250849 hom.)
• Consequence: INVS NM_014425.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.242
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-100297194-A-G is Benign according to our data. Variant chr9-100297194-A-G is described in ClinVar as Benign. ClinVar VariationId is 260414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014425.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	NM_014425.5	MANE Select	c.3016+48A>G		intron	N/A	NP_055240.2
	INVS	NM_001318381.2		c.2728+48A>G		intron	N/A	NP_001305310.1
	INVS	NM_001318382.2		c.2038+48A>G		intron	N/A	NP_001305311.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.3016+48A>G		intron	N/A	ENSP00000262457.2
	INVS	ENST00000262456.6	TSL:5	c.2506+48A>G		intron	N/A	ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.671 AC: 102015 AN: 151952 Hom.: 34874 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.895

Gnomad SAS AF: 0.784

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.590

Gnomad OTH AF: 0.655

GnomAD2 exomes AF: 0.686 AC: 156491 AN: 227998 AF XY: 0.681

Gnomad AFR exome AF: 0.762

Gnomad AMR exome AF: 0.819

Gnomad ASJ exome AF: 0.654

Gnomad EAS exome AF: 0.896

Gnomad FIN exome AF: 0.639

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.644

GnomAD4 exome AF: 0.628 AC: 782741 AN: 1247226 Hom.: 250849 Cov.: 17 AF XY: 0.630 AC XY: 396999 AN XY: 629986

African (AFR) AF: 0.761 AC: 22099 AN: 29040

American (AMR) AF: 0.809 AC: 34528 AN: 42654

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 16062 AN: 24586

East Asian (EAS) AF: 0.919 AC: 34663 AN: 37698

South Asian (SAS) AF: 0.771 AC: 62135 AN: 80632

European-Finnish (FIN) AF: 0.629 AC: 33036 AN: 52542

Middle Eastern (MID) AF: 0.647 AC: 3423 AN: 5290

European-Non Finnish (NFE) AF: 0.588 AC: 542298 AN: 921536

Other (OTH) AF: 0.648 AC: 34497 AN: 53248

GnomAD4 genome AF: 0.671 AC: 102088 AN: 152070 Hom.: 34892 Cov.: 32 AF XY: 0.678 AC XY: 50427 AN XY: 74340

African (AFR) AF: 0.756 AC: 31377 AN: 41490

American (AMR) AF: 0.727 AC: 11120 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2317 AN: 3470

East Asian (EAS) AF: 0.895 AC: 4603 AN: 5144

South Asian (SAS) AF: 0.783 AC: 3772 AN: 4818

European-Finnish (FIN) AF: 0.652 AC: 6888 AN: 10566

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.590 AC: 40090 AN: 67982

Other (OTH) AF: 0.653 AC: 1380 AN: 2114

Alfa AF: 0.605 Hom.: 4718

Bravo AF: 0.679

Asia WGS AF: 0.791 AC: 2751 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.4
DANN	Benign	0.48
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7864494; hg19: chr9-103059476;