chr9-100104595-G-A

Position:

• chr9-100104595-G-A

Variant summary

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

The NM_014425.5(INVS):​c.74G>A​(p.Gly25Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INVS NM_014425.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

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]

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, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.74G>A	p.Gly25Glu	missense_variant	2/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.-303G>A		5_prime_UTR_variant	2/18		NP_001305310.1
INVS	NM_001318382.2	c.-916G>A		5_prime_UTR_variant	2/17		NP_001305311.1
INVS	NR_134606.2	n.272G>A		non_coding_transcript_exon_variant	2/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.74G>A	p.Gly25Glu	missense_variant	2/17	1	NM_014425.5	ENSP00000262457.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.74G>A (p.G25E) alteration is located in exon 2 (coding exon 1) of the INVS gene. This alteration results from a G to A substitution at nucleotide position 74, causing the glycine (G) at amino acid position 25 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	2.9	M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.0030	D;D;T
Polyphen		1.0	D;D;.
Vest4		0.80
MutPred		0.57		Gain of solvent accessibility (P = 0.0596);Gain of solvent accessibility (P = 0.0596);Gain of solvent accessibility (P = 0.0596);
MVP		0.93
MPC		0.97
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.80

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-102866877;