rs143020939

Variant names:

• chr1-5874521-C-A
• rs143020939
• NM_015102.5:c.3181G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-5874521-C-A
• chr1-5874521-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015102.5(NPHP4):​c.3181G>T​(p.Val1061Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1061I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.126
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3181G>T	p.Val1061Phe	missense	Exon 22 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1645G>T	p.Val549Phe	missense	Exon 18 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1642G>T	p.Val548Phe	missense	Exon 19 of 27	NP_001278522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3181G>T	p.Val1061Phe	missense	Exon 22 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2082G>T		non_coding_transcript_exon	Exon 19 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*992G>T		non_coding_transcript_exon	Exon 25 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3181G>T (p.V1061F) alteration is located in exon 22 (coding exon 21) of the NPHP4 gene. This alteration results from a G to T substitution at nucleotide position 3181, causing the valine (V) at amino acid position 1061 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.0024	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.3	L
PhyloP100		-0.13
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.079	T
Polyphen		0.82	P
Vest4		0.74
MutPred		0.44		Gain of catalytic residue at V1061 (P = 0.0548)
MVP		0.61
MPC		0.10
ClinPred		0.80	D
GERP RS		-5.5
Varity_R		0.31
gMVP		0.82
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143020939; hg19: chr1-5934581;