rs147452898

Variant names:

• chr9-100284483-G-C
• rs147452898
• NM_014425.5:c.1948G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014425.5(INVS):​c.1948G>C​(p.Ala650Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 1,614,130 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A650A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (25 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.716
• Publications: 4 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

LOC124902235 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009577215).
• BP6: Variant 9-100284483-G-C is Benign according to our data. Variant chr9-100284483-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00375 (571/152360) while in subpopulation NFE AF = 0.00404 (275/68036). AF 95% confidence interval is 0.00365. There are 4 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1948G>C	p.Ala650Pro	missense	Exon 13 of 17	NP_055240.2
	INVS	NM_001318381.2		c.1660G>C	p.Ala554Pro	missense	Exon 14 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.970G>C	p.Ala324Pro	missense	Exon 13 of 17	NP_001305311.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INVS	ENST00000262457.7	TSL:1 MANE Select	c.1948G>C	p.Ala650Pro	missense	Exon 13 of 17	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000885857.1		c.1948G>C	p.Ala650Pro	missense	Exon 14 of 18	ENSP00000555916.1
	INVS	ENST00000885859.1		c.1948G>C	p.Ala650Pro	missense	Exon 14 of 18	ENSP00000555918.1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152242 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00399 AC: 998 AN: 250398 AF XY: 0.00391

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00425 AC: 6217 AN: 1461770 Hom.: 25 Cov.: 31 AF XY: 0.00412 AC XY: 2997 AN XY: 727188

African (AFR) AF: 0.000597 AC: 20 AN: 33474

American (AMR) AF: 0.000828 AC: 37 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86254

European-Finnish (FIN) AF: 0.0188 AC: 1004 AN: 53398

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.00440 AC: 4889 AN: 1111968

Other (OTH) AF: 0.00361 AC: 218 AN: 60382

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152360 Hom.: 4 Cov.: 33 AF XY: 0.00415 AC XY: 309 AN XY: 74512

African (AFR) AF: 0.000817 AC: 34 AN: 41600

American (AMR) AF: 0.00183 AC: 28 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0213 AC: 226 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00319 Hom.: 0

Bravo AF: 0.00227

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00330 AC: 400

EpiCase AF: 0.00344

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Infantile nephronophthisis (3)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.72
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.23
Sift	Benign	0.076	T
Sift4G	Benign	0.16	T
Polyphen		0.17	B
Vest4		0.19
MVP		0.37
MPC		0.46
ClinPred		0.011	T
GERP RS		-2.3
Varity_R		0.084
gMVP		0.15
Mutation Taster		=96/4	polymorphism

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: rs147452898; hg19: chr9-103046765;