rs201998215

Variant names:

• chr1-5978292-G-A
• rs201998215
• NM_015102.5:c.257C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-5978292-G-A
• chr1-5978292-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001291593.2(NPHP4):​c.-973C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,608,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: NPHP4 NM_001291593.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 0.850
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08985978).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000269 (41/152152) while in subpopulation AMR AF = 0.0017 (26/15286). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291593.2. 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.257C>T	p.Pro86Leu	missense	Exon 3 of 30	NP_055917.1
	NPHP4	NM_001291593.2		c.-973C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 27	NP_001278522.1
	NPHP4	NM_001291593.2		c.-973C>T		5_prime_UTR	Exon 3 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.257C>T	p.Pro86Leu	missense	Exon 3 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.257C>T		non_coding_transcript_exon	Exon 3 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.257C>T		non_coding_transcript_exon	Exon 3 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152034 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000130 AC: 31 AN: 239128 AF XY: 0.000108

Gnomad AFR exome AF: 0.000276

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 276 AN: 1455950 Hom.: 0 Cov.: 31 AF XY: 0.000181 AC XY: 131 AN XY: 723760

African (AFR) AF: 0.000150 AC: 5 AN: 33386

American (AMR) AF: 0.000364 AC: 16 AN: 43926

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39510

South Asian (SAS) AF: 0.00 AC: 0 AN: 85234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000224 AC: 248 AN: 1109608

Other (OTH) AF: 0.000116 AC: 7 AN: 60186

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152152 Hom.: 0 Cov.: 29 AF XY: 0.000296 AC XY: 22 AN XY: 74374

African (AFR) AF: 0.000145 AC: 6 AN: 41500

American (AMR) AF: 0.00170 AC: 26 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

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: 0.000118 AC: 8 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.000344

ESP6500AA AF: 0.000486 AC: 2

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Kidney disorder (1)
-	1	-	Nephronophthisis (1)
-	1	-	Nephronophthisis 4 (1)
-	1	-	NPHP4-related disorder (1)
-	1	-	Optic atrophy (1)
-	1	-	Retinal dystrophy (1)
-	1	-	Senior-Loken syndrome 4 (1)
-	1	-	Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.85
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.010	D
Polyphen		0.97	D
Vest4		0.19
MVP		0.88
MPC		0.069
ClinPred		0.053	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.32
Mutation Taster		=97/3	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: rs201998215; hg19: chr1-6038352; COSMIC: COSV106111147;