rs116438342

chr9-100246622-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_014425.5(INVS):c.913G>A(p.Val305Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V305G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.99

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 -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01483497).
• BP6: Variant 9-100246622-G-A is Benign according to our data. Variant chr9-100246622-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 198857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100246622-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00133 (202/152324) while in subpopulation AFR AF= 0.00462 (192/41566). AF 95% confidence interval is 0.00408. There are 1 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INVS	NM_014425.5	c.913G>A	p.Val305Ile	missense_variant	8/17	ENST00000262457.7
INVS	NM_001318381.2	c.625G>A	p.Val209Ile	missense_variant	9/18
INVS	NM_001318382.2	c.-66G>A		5_prime_UTR_variant	8/17
INVS	NR_134606.2	n.1111G>A		non_coding_transcript_exon_variant	8/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INVS	ENST00000262457.7	c.913G>A	p.Val305Ile	missense_variant	8/17	1	NM_014425.5	A2
INVS	ENST00000262456.6	c.913G>A	p.Val305Ile	missense_variant	8/18	5		P4

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000331 AC: 83 AN: 250884 Hom.: 1 AF XY: 0.000243 AC XY: 33 AN XY: 135592

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.000116

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: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1460810 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 81 AN XY: 726746

Gnomad4 AFR exome AF: 0.00365

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74480

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.00156

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000436 AC: 53

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Infantile nephronophthisis Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 02, 2015

- -

Nephronophthisis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.28
Sift	Benign	0.046	D;T
Sift4G	Benign	0.064	T;T
Polyphen		0.87	P;P
Vest4		0.79
MVP		0.83
MPC		0.72
ClinPred		0.072	T
GERP RS		5.5
Varity_R		0.18
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs116438342; hg19: chr9-103008904;