rs10989019

Variant names:

• chr9-100214259-T-C
• rs10989019
• NM_014425.5:c.274-11803T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014425.5(INVS):​c.274-11803T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 152,126 control chromosomes in the GnomAD database, including 4,580 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.19 (4580 hom., cov: 31)
• Consequence: INVS NM_014425.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.284
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5	c.274-11803T>C		intron_variant	Intron 3 of 16	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.-103-1142T>C		intron_variant	Intron 3 of 17		NP_001305310.1
INVS	NM_001318382.2	c.-716-11803T>C		intron_variant	Intron 3 of 16		NP_001305311.1
INVS	NR_134606.2	n.472-11803T>C		intron_variant	Intron 3 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.274-11803T>C		intron_variant	Intron 3 of 16	1	NM_014425.5	ENSP00000262457.2

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29492 AN: 152008 Hom.: 4566 Cov.: 31

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.159

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 29549 AN: 152126 Hom.: 4580 Cov.: 31 AF XY: 0.190 AC XY: 14122 AN XY: 74410

African (AFR) AF: 0.435 AC: 18046 AN: 41438

American (AMR) AF: 0.110 AC: 1685 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3472

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5184

South Asian (SAS) AF: 0.0425 AC: 205 AN: 4826

European-Finnish (FIN) AF: 0.146 AC: 1543 AN: 10598

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7414 AN: 68012

Other (OTH) AF: 0.157 AC: 330 AN: 2108

Alfa AF: 0.158 Hom.: 2579

Bravo AF: 0.201

Asia WGS AF: 0.0480 AC: 169 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.4
DANN	Benign	0.48
PhyloP100		-0.28
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: rs10989019; hg19: chr9-102976541;