rs1553186265

Positions:

• chr1-5948172-AAGCCCAGACCATTGTGCAC-AG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_015102.5(NPHP4):​c.871_889delGTGCACAATGGTCTGGGCTinsC​(p.Val291_Phe297delinsLeu) variant causes a missense, conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NPHP4 NM_015102.5 missense, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 6.07

Genes affected

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

NPHP4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_015102.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.871_889delGTGCACAATGGTCTGGGCTinsC	p.Val291_Phe297delinsLeu	missense_variant, conservative_inframe_deletion	8/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.871_889delGTGCACAATGGTCTGGGCTinsC	p.Val291_Phe297delinsLeu	missense_variant, conservative_inframe_deletion	8/30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.734_752delGTGCACAATGGTCTGGGCTinsC		non_coding_transcript_exon_variant	7/27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.871_889delGTGCACAATGGTCTGGGCTinsC		non_coding_transcript_exon_variant	8/33	2		ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Nephronophthisis Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Feb 21, 2018	This individual is heterozygous for the c.871_889delinsC variant in the NPHP4 gene. This in-frame variant results in the replacement of 7 amino acids Val291 to Phe297 with a single leucine residue. This variant has not been reported in any population databases (i.e. ExAC, ESP or dbSNP). To our knowledge, this variant has not been previously reported in the literature or any disease specific databases. This variant is considered to be a variant of uncertain significance (VOUS) according to the ACMG guidelines. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2018	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the disrupted amino acids is currently unknown. This variant has not been reported in the literature in individuals with NPHP4-related disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.871_889delinsC, is a complex sequence change that results in the deletion of 7 amino acids and the insertion of 1 amino acid to the NPHP4 protein (p.Val291_Phe297delinsLeu), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553186265; hg19: chr1-6008233;