9-100126595-C-T

Variant names:

• chr9-100126595-C-T
• rs76975466
• NM_014425.5:c.273+46C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014425.5(INVS):​c.273+46C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,560,734 control chromosomes in the GnomAD database, including 1,692 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (155 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1537 hom.)
• Consequence: INVS NM_014425.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.00
• Publications: 0 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=-0.82).
• BP6: Variant 9-100126595-C-T is Benign according to our data. Variant chr9-100126595-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0339 (5154/152228) while in subpopulation NFE AF = 0.0466 (3172/68018). AF 95% confidence interval is 0.0453. There are 155 homozygotes in GnomAd4. There are 2612 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 155 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5	c.273+46C>T		intron_variant	Intron 3 of 16	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.-104+46C>T		intron_variant	Intron 3 of 17		NP_001305310.1
INVS	NM_001318382.2	c.-717+46C>T		intron_variant	Intron 3 of 16		NP_001305311.1
INVS	NR_134606.2	n.471+46C>T		intron_variant	Intron 3 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.273+46C>T		intron_variant	Intron 3 of 16	1	NM_014425.5	ENSP00000262457.2

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5155 AN: 152110 Hom.: 155 Cov.: 32

Gnomad AFR AF: 0.00751

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0368 AC: 9146 AN: 248582 AF XY: 0.0376

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0323

GnomAD4 exome AF: 0.0423 AC: 59647 AN: 1408506 Hom.: 1537 Cov.: 23 AF XY: 0.0415 AC XY: 29192 AN XY: 703874

African (AFR) AF: 0.00633 AC: 205 AN: 32390

American (AMR) AF: 0.0120 AC: 535 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 336 AN: 25810

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39406

South Asian (SAS) AF: 0.0170 AC: 1447 AN: 85006

European-Finnish (FIN) AF: 0.105 AC: 5572 AN: 52926

Middle Eastern (MID) AF: 0.0148 AC: 84 AN: 5674

European-Non Finnish (NFE) AF: 0.0464 AC: 49357 AN: 1063982

Other (OTH) AF: 0.0359 AC: 2110 AN: 58706

GnomAD4 genome AF: 0.0339 AC: 5154 AN: 152228 Hom.: 155 Cov.: 32 AF XY: 0.0351 AC XY: 2612 AN XY: 74436

African (AFR) AF: 0.00746 AC: 310 AN: 41542

American (AMR) AF: 0.0155 AC: 237 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4822

European-Finnish (FIN) AF: 0.115 AC: 1214 AN: 10580

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3172 AN: 68018

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0407 Hom.: 248

Bravo AF: 0.0251

Asia WGS AF: 0.00751 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely 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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.7
DANN	Benign	0.22
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76975466; hg19: chr9-102888877;