9-100104613-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014425.5(INVS):c.92A>G(p.Gln31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2309778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.92A>G	p.Gln31Arg	missense_variant	2/17	ENST00000262457.7
INVS	NM_001318381.2	c.-285A>G		5_prime_UTR_variant	2/18
INVS	NM_001318382.2	c.-898A>G		5_prime_UTR_variant	2/17
INVS	NR_134606.2	n.290A>G		non_coding_transcript_exon_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.92A>G	p.Gln31Arg	missense_variant	2/17	1	NM_014425.5	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460764 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726778

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1398336). This variant has not been reported in the literature in individuals affected with INVS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 31 of the INVS protein (p.Gln31Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.38	T;.;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T;T;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.84	N;N;N
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.57	P;P;.
Vest4		0.27
MutPred		0.53		Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);Gain of MoRF binding (P = 0.0285);
MVP		0.76
MPC		0.25
ClinPred		0.45	T
GERP RS		5.5
Varity_R		0.082
gMVP		0.34

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: rs1003287751; hg19: chr9-102866895;