1-5874581-A-G

Variant names:

• chr1-5874581-A-G
• rs1642364275
• NM_015102.5:c.3121T>C
• NPHP4 p.Phe1041Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015102.5(NPHP4):​c.3121T>C​(p.Phe1041Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1041S) 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: 8.60
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3121T>C	p.Phe1041Leu	missense	Exon 22 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1585T>C	p.Phe529Leu	missense	Exon 18 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1582T>C	p.Phe528Leu	missense	Exon 19 of 27	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3121T>C	p.Phe1041Leu	missense	Exon 22 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*2022T>C		non_coding_transcript_exon	Exon 19 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*932T>C		non_coding_transcript_exon	Exon 25 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nephronophthisis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		8.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.044	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.77
Mutation Taster		=32/68	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1642364275;

hg19: chr1-5934641;