chr9-100104505-C-T

Variant names:

• chr9-100104505-C-T
• rs181463817
• NM_014425.5:c.-17C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_014425.5(INVS):​c.-17C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,580,822 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: INVS NM_014425.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.541
• Publications: 1 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, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 9-100104505-C-T is Benign according to our data. Variant chr9-100104505-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95593.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00177 (270/152276) while in subpopulation AFR AF = 0.00619 (257/41538). AF 95% confidence interval is 0.00557. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014425.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	NM_014425.5	MANE Select	c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	NP_055240.2
	INVS	NM_014425.5	MANE Select	c.-17C>T		5_prime_UTR	Exon 2 of 17	NP_055240.2
	INVS	NM_001318381.2		c.-393C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001305310.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000374921.3	TSL:1	c.-17C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000364056.3	Q9Y283-3
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.-17C>T		5_prime_UTR	Exon 2 of 17	ENSP00000262457.2	Q9Y283-1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000531 AC: 133 AN: 250314 AF XY: 0.000414

Gnomad AFR exome AF: 0.00655

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000210 AC: 300 AN: 1428546 Hom.: 1 Cov.: 27 AF XY: 0.000196 AC XY: 140 AN XY: 712940

African (AFR) AF: 0.00729 AC: 239 AN: 32774

American (AMR) AF: 0.000448 AC: 20 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.000304 AC: 12 AN: 39530

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.00000647 AC: 7 AN: 1081900

Other (OTH) AF: 0.000320 AC: 19 AN: 59284

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00162 AC XY: 121 AN XY: 74468

African (AFR) AF: 0.00619 AC: 257 AN: 41538

American (AMR) AF: 0.000719 AC: 11 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000940 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile nephronophthisis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.64
PhyloP100		0.54
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0

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: rs181463817; hg19: chr9-102866787; COSMIC: COSV99317314; COSMIC: COSV99317314;