9-100099286-C-T

Position:

• chr9-100099286-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014425.5(INVS):​c.-155C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00899 in 160,600 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (1 hom.)
• Consequence: INVS NM_014425.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.928

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-100099286-C-T is Benign according to our data. Variant chr9-100099286-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 364218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00871 (1327/152302) while in subpopulation SAS AF= 0.0267 (129/4826). AF 95% confidence interval is 0.023. There are 19 homozygotes in gnomad4. There are 673 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.-155C>T		5_prime_UTR_variant	1/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.-531C>T		5_prime_UTR_variant	1/18		NP_001305310.1
INVS	NM_001318382.2	c.-1144C>T		5_prime_UTR_variant	1/17		NP_001305311.1
INVS	NR_134606.2	n.44C>T		non_coding_transcript_exon_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.-155C>T		5_prime_UTR_variant	1/17	1	NM_014425.5	ENSP00000262457	A2

Frequencies

GnomAD3 genomes AF: 0.00873 AC: 1329 AN: 152184 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0271

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0129

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0141 AC: 117 AN: 8298 Hom.: 1 Cov.: 0 AF XY: 0.0181 AC XY: 87 AN XY: 4812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0250

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0273

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00933

Gnomad4 OTH exome AF: 0.00820

GnomAD4 genome AF: 0.00871 AC: 1327 AN: 152302 Hom.: 19 Cov.: 32 AF XY: 0.00904 AC XY: 673 AN XY: 74464

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.0268

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.00376

Gnomad4 NFE AF: 0.0129

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0102 Hom.: 3

Bravo AF: 0.00812

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Infantile nephronophthisis Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.85

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: rs62577237; hg19: chr9-102861568;