chr9-100252956-T-C

Position:

• chr9-100252956-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014425.5(INVS):​c.1284T>C​(p.His428=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,613,976 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: INVS NM_014425.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-100252956-T-C is Benign according to our data. Variant chr9-100252956-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-100252956-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00344 (524/152288) while in subpopulation AFR AF= 0.0119 (496/41556). AF 95% confidence interval is 0.0111. There are 1 homozygotes in gnomad4. There are 253 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
INVS	NM_014425.5	c.1284T>C	p.His428=	synonymous_variant	10/17	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.996T>C	p.His332=	synonymous_variant	11/18		NP_001305310.1
INVS	NM_001318382.2	c.306T>C	p.His102=	synonymous_variant	10/17		NP_001305311.1
INVS	NR_134606.2	n.1482T>C		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>C	p.His428=	synonymous_variant	10/17	1	NM_014425.5	ENSP00000262457	A2
INVS	ENST00000262456.6	c.1284T>C	p.His428=	synonymous_variant	10/18	5		ENSP00000262456	P4

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.000856 AC: 215 AN: 251168 Hom.: 0 AF XY: 0.000663 AC XY: 90 AN XY: 135728

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000356 AC: 520 AN: 1461688 Hom.: 5 Cov.: 32 AF XY: 0.000315 AC XY: 229 AN XY: 727150

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.00344 AC: 524 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74476

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00390

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 06, 2017

- -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.39
DANN	Benign	0.60

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

LitVar

Other links and lift over

dbSNP: rs77465715; hg19: chr9-103015238;