rs61147858

Variant names:

• chr9-100226046-CTT-C
• rs61147858
• NM_014425.5:c.274-15_274-14delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014425.5(INVS):​c.274-15_274-14delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,598,052 control chromosomes in the GnomAD database, including 13,730 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3603 hom., cov: 28)
  • Exomes 𝑓: 0.11 (10127 hom.)
• Consequence: INVS NM_014425.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.960
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 9-100226046-CTT-C is Benign according to our data. Variant chr9-100226046-CTT-C is described in ClinVar as Benign. ClinVar VariationId is 260412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.378 is higher than 0.05.

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.274-15_274-14delTT		intron	N/A	NP_055240.2
	INVS	NM_001318381.2		c.-15-15_-15-14delTT		intron	N/A	NP_001305310.1
	INVS	NM_001318382.2		c.-716-15_-716-14delTT		intron	N/A	NP_001305311.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.274-15_274-14delTT		intron	N/A	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000885857.1		c.274-15_274-14delTT		intron	N/A	ENSP00000555916.1
	INVS	ENST00000885859.1		c.274-15_274-14delTT		intron	N/A	ENSP00000555918.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26828 AN: 151838 Hom.: 3592 Cov.: 28

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0427

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.102 AC: 23843 AN: 234502 AF XY: 0.0961

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.0576

Gnomad ASJ exome AF: 0.0477

Gnomad EAS exome AF: 0.00131

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0955

GnomAD4 exome AF: 0.106 AC: 153033 AN: 1446096 Hom.: 10127 AF XY: 0.103 AC XY: 73845 AN XY: 718658

African (AFR) AF: 0.388 AC: 12832 AN: 33062

American (AMR) AF: 0.0637 AC: 2764 AN: 43394

Ashkenazi Jewish (ASJ) AF: 0.0464 AC: 1197 AN: 25814

East Asian (EAS) AF: 0.000885 AC: 35 AN: 39560

South Asian (SAS) AF: 0.0433 AC: 3649 AN: 84182

European-Finnish (FIN) AF: 0.136 AC: 7186 AN: 52924

Middle Eastern (MID) AF: 0.0734 AC: 408 AN: 5556

European-Non Finnish (NFE) AF: 0.107 AC: 118430 AN: 1101762

Other (OTH) AF: 0.109 AC: 6532 AN: 59842

GnomAD4 genome AF: 0.177 AC: 26876 AN: 151956 Hom.: 3603 Cov.: 28 AF XY: 0.173 AC XY: 12878 AN XY: 74304

African (AFR) AF: 0.383 AC: 15851 AN: 41358

American (AMR) AF: 0.104 AC: 1582 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3470

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4818

European-Finnish (FIN) AF: 0.145 AC: 1528 AN: 10550

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7133 AN: 67996

Other (OTH) AF: 0.141 AC: 296 AN: 2104

Alfa AF: 0.129 Hom.: 342

Bravo AF: 0.182

Asia WGS AF: 0.0460 AC: 162 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis (2)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.96
Mutation Taster		=11/89	disease causing (long InDel)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61147858; hg19: chr9-102988328;