9-100296933-C-T

Position:

• chr9-100296933-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014425.5(INVS):​c.2803C>T​(p.His935Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,614,000 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H935Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (14 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.712

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007744968).
• BP6: Variant 9-100296933-C-T is Benign according to our data. Variant chr9-100296933-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr9-100296933-C-T is described in Lovd as [Benign]. Variant chr9-100296933-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00233 (355/152254) while in subpopulation NFE AF= 0.00378 (257/68012). AF 95% confidence interval is 0.0034. There are 0 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.2803C>T	p.His935Tyr	missense_variant	15/17	ENST00000262457.7
INVS	NM_001318381.2	c.2515C>T	p.His839Tyr	missense_variant	16/18
INVS	NM_001318382.2	c.1825C>T	p.His609Tyr	missense_variant	15/17
INVS	NR_134606.2	n.2952C>T		non_coding_transcript_exon_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.2803C>T	p.His935Tyr	missense_variant	15/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.2293C>T	p.His765Tyr	missense_variant	16/18	5		P4

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 355 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00378

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00252 AC: 632 AN: 251282 Hom.: 2 AF XY: 0.00277 AC XY: 376 AN XY: 135790

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00337

Gnomad FIN exome AF: 0.00259

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00285 AC: 4167 AN: 1461746 Hom.: 14 Cov.: 32 AF XY: 0.00282 AC XY: 2049 AN XY: 727172

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00336

Gnomad4 FIN exome AF: 0.00187

Gnomad4 NFE exome AF: 0.00317

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00233 AC: 355 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00228 AC XY: 170 AN XY: 74456

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00300 Hom.: 2

Bravo AF: 0.00200

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00397

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Infantile nephronophthisis Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 12, 2016

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

INVS: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.82	T;D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.051
Sift	Uncertain	0.014	D;D
Sift4G	Uncertain	0.051	T;D
Polyphen		0.52	P;B
Vest4		0.26
MVP		0.63
MPC		0.54
ClinPred		0.020	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.081

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: rs139768159; hg19: chr9-103059215; COSMIC: COSV105106169;