rs41312220

Variant names:

• chr9-100240184-A-G
• rs41312220
• NM_014425.5:c.740A>G

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.740A>G​(p.Asn247Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00565 in 1,613,976 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (35 hom.)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.27
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009686917).
• BP6: Variant 9-100240184-A-G is Benign according to our data. Variant chr9-100240184-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95600.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 = 0.00503 (765/152234) while in subpopulation NFE AF = 0.00768 (522/68006). AF 95% confidence interval is 0.00713. There are 1 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 35 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.740A>G	p.Asn247Ser	missense	Exon 6 of 17	NP_055240.2
	INVS	NM_001318381.2		c.452A>G	p.Asn151Ser	missense	Exon 7 of 18	NP_001305310.1
	INVS	NM_001318382.2		c.-250A>G		5_prime_UTR	Exon 6 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.740A>G	p.Asn247Ser	missense	Exon 6 of 17	ENSP00000262457.2	Q9Y283-1
	INVS	ENST00000885857.1		c.740A>G	p.Asn247Ser	missense	Exon 7 of 18	ENSP00000555916.1
	INVS	ENST00000885859.1		c.740A>G	p.Asn247Ser	missense	Exon 7 of 18	ENSP00000555918.1

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 765 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00767

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00481 AC: 1209 AN: 251430 AF XY: 0.00483

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00565

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0112

Gnomad NFE exome AF: 0.00696

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00571 AC: 8349 AN: 1461742 Hom.: 35 Cov.: 31 AF XY: 0.00571 AC XY: 4154 AN XY: 727172

African (AFR) AF: 0.000926 AC: 31 AN: 33476

American (AMR) AF: 0.00190 AC: 85 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00540 AC: 141 AN: 26134

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

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.0112 AC: 596 AN: 53414

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00643 AC: 7151 AN: 1111886

Other (OTH) AF: 0.00525 AC: 317 AN: 60390

GnomAD4 genome AF: 0.00503 AC: 765 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74440

African (AFR) AF: 0.000842 AC: 35 AN: 41562

American (AMR) AF: 0.00314 AC: 48 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0124 AC: 131 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00768 AC: 522 AN: 68006

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00614 Hom.: 8

Bravo AF: 0.00408

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00475 AC: 577

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00709

EpiControl AF: 0.00599

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Benign	0.071	T
Sift4G	Benign	0.089	T
Polyphen		0.25	B
Vest4		0.38
MVP		0.72
MPC		0.36
ClinPred		0.034	T
GERP RS		5.6
Varity_R		0.17
gMVP		0.26
Mutation Taster		=95/5	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: rs41312220; hg19: chr9-103002466; COSMIC: COSV99075705; COSMIC: COSV99075705;