1-5877331-C-T

Variant names:

• chr1-5877331-C-T
• rs3747989
• NM_015102.5:c.2612-33G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):​c.2612-33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 1,538,150 control chromosomes in the GnomAD database, including 498,982 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (52889 hom., cov: 35)
  • Exomes 𝑓: 0.80 (446093 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.49
• Publications: 9 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: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.97).
• BP6: Variant 1-5877331-C-T is Benign according to our data. Variant chr1-5877331-C-T is described in ClinVar as Benign. ClinVar VariationId is 260547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

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.2612-33G>A		intron	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1076-33G>A		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.1073-33G>A		intron	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.2612-33G>A		intron	N/A	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1513-33G>A		intron	N/A	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*160-33G>A		intron	N/A	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.831 AC: 126514 AN: 152162 Hom.: 52841 Cov.: 35

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.772

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.798

Gnomad OTH AF: 0.833

GnomAD2 exomes AF: 0.795 AC: 153869 AN: 193452 AF XY: 0.794

Gnomad AFR exome AF: 0.938

Gnomad AMR exome AF: 0.731

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.852

Gnomad FIN exome AF: 0.793

Gnomad NFE exome AF: 0.801

Gnomad OTH exome AF: 0.796

GnomAD4 exome AF: 0.802 AC: 1111226 AN: 1385870 Hom.: 446093 Cov.: 27 AF XY: 0.800 AC XY: 543862 AN XY: 679984

African (AFR) AF: 0.936 AC: 30262 AN: 32322

American (AMR) AF: 0.739 AC: 28967 AN: 39202

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 20247 AN: 24480

East Asian (EAS) AF: 0.836 AC: 31020 AN: 37126

South Asian (SAS) AF: 0.736 AC: 57401 AN: 77972

European-Finnish (FIN) AF: 0.793 AC: 40210 AN: 50698

Middle Eastern (MID) AF: 0.786 AC: 4358 AN: 5548

European-Non Finnish (NFE) AF: 0.803 AC: 852654 AN: 1061372

Other (OTH) AF: 0.807 AC: 46107 AN: 57150

GnomAD4 genome AF: 0.832 AC: 126624 AN: 152280 Hom.: 52889 Cov.: 35 AF XY: 0.828 AC XY: 61648 AN XY: 74444

African (AFR) AF: 0.933 AC: 38797 AN: 41592

American (AMR) AF: 0.772 AC: 11812 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2884 AN: 3472

East Asian (EAS) AF: 0.835 AC: 4311 AN: 5160

South Asian (SAS) AF: 0.738 AC: 3565 AN: 4832

European-Finnish (FIN) AF: 0.783 AC: 8298 AN: 10602

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.798 AC: 54298 AN: 68004

Other (OTH) AF: 0.835 AC: 1762 AN: 2110

Alfa AF: 0.809 Hom.: 9189

Bravo AF: 0.838

Asia WGS AF: 0.758 AC: 2636 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephronophthisis 4 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.097
DANN	Benign	0.58
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3747989; hg19: chr1-5937391;