rs115640267

chr9-100104623-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014425.5(INVS):c.102C>T(p.Ile34=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000999 in 1,607,312 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (11 hom.)
• Consequence: INVS NM_014425.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 9-100104623-C-T is Benign according to our data. Variant chr9-100104623-C-T is described in ClinVar as [Benign]. Clinvar id is 167194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00512 (780/152232) while in subpopulation AFR AF= 0.0178 (740/41546). AF 95% confidence interval is 0.0167. There are 2 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.102C>T	p.Ile34=	synonymous_variant	2/17	ENST00000262457.7
INVS	NM_001318381.2	c.-275C>T		5_prime_UTR_variant	2/18
INVS	NM_001318382.2	c.-888C>T		5_prime_UTR_variant	2/17
INVS	NR_134606.2	n.300C>T		non_coding_transcript_exon_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.102C>T	p.Ile34=	synonymous_variant	2/17	1	NM_014425.5	A2

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00148 AC: 371 AN: 251412 Hom.: 1 AF XY: 0.00110 AC XY: 150 AN XY: 135884

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000567 AC: 825 AN: 1455080 Hom.: 11 Cov.: 28 AF XY: 0.000490 AC XY: 355 AN XY: 724296

Gnomad4 AFR exome AF: 0.0180

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.0000767

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000968

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00512 AC: 780 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00472 AC XY: 351 AN XY: 74440

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00320 Hom.: 3

Bravo AF: 0.00625

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2014	- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	9.3
Dann	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs115640267; hg19: chr9-102866905;