9-100252956-T-G

Position:

• chr9-100252956-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014425.5(INVS):​c.1284T>G​(p.His428Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H428H) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.1284T>G	p.His428Gln	missense_variant	10/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.996T>G	p.His332Gln	missense_variant	11/18		NP_001305310.1
INVS	NM_001318382.2	c.306T>G	p.His102Gln	missense_variant	10/17		NP_001305311.1
INVS	NR_134606.2	n.1482T>G		non_coding_transcript_exon_variant	10/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.1284T>G	p.His428Gln	missense_variant	10/17	1	NM_014425.5	ENSP00000262457.2
INVS	ENST00000262456.6	c.1284T>G	p.His428Gln	missense_variant	10/18	5		ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.0011	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.82		Gain of helix (P = 0.2294);Gain of helix (P = 0.2294);
MVP		0.76
MPC		0.85
ClinPred		1.0	D
GERP RS		-3.6
Varity_R		0.83
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77465715; hg19: chr9-103015238;