rs145255635

Variant names:

• chr1-5905773-G-A
• rs145255635
• NM_015102.5:c.1622C>T
• NPHP4 p.Pro541Leu

Your query was ambiguous. Multiple possible variants found:

• chr1-5905773-G-A
• chr1-5905773-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.1622C>T​(p.Pro541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,607,132 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P541P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.48
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057252645).
• BP6: Variant 1-5905773-G-A is Benign according to our data. Variant chr1-5905773-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00246 (374/152252) while in subpopulation AFR AF = 0.00852 (354/41530). AF 95% confidence interval is 0.00779. There are 3 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1622C>T	p.Pro541Leu	missense	Exon 14 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.86C>T	p.Pro29Leu	missense	Exon 10 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.83C>T	p.Pro28Leu	missense	Exon 11 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.1622C>T	p.Pro541Leu	missense	Exon 14 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*523C>T		non_coding_transcript_exon	Exon 11 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.1619C>T		non_coding_transcript_exon	Exon 14 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152134 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00855

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000673 AC: 158 AN: 234828 AF XY: 0.000550

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.000635

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000344 AC: 501 AN: 1454880 Hom.: 3 Cov.: 32 AF XY: 0.000306 AC XY: 221 AN XY: 722982

African (AFR) AF: 0.00894 AC: 298 AN: 33316

American (AMR) AF: 0.000708 AC: 31 AN: 43774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39414

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53006

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5762

European-Non Finnish (NFE) AF: 0.000113 AC: 125 AN: 1108708

Other (OTH) AF: 0.000615 AC: 37 AN: 60144

GnomAD4 genome AF: 0.00246 AC: 374 AN: 152252 Hom.: 3 Cov.: 33 AF XY: 0.00224 AC XY: 167 AN XY: 74466

African (AFR) AF: 0.00852 AC: 354 AN: 41530

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000960 Hom.: 2

Bravo AF: 0.00266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Nephronophthisis 4 (3)
-	-	1	Lynch syndrome 1 (1)
-	-	1	Nephronophthisis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	NPHP4-related disorder (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	12
DANN	Benign	0.67
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.5
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Benign	0.090	T
Sift4G	Benign	0.31	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.35
Mutation Taster		=30/70	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: rs145255635;

hg19: chr1-5965833;