rs905467

chr1-5874440-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):c.3231+31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,486,024 control chromosomes in the GnomAD database, including 47,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3940 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43410 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-5874440-T-C is Benign according to our data. Variant chr1-5874440-T-C is described in ClinVar as [Benign]. Clinvar id is 260553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP4	NM_015102.5	c.3231+31A>G		intron_variant		ENST00000378156.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP4	ENST00000378156.9	c.3231+31A>G		intron_variant		1	NM_015102.5	P2
NPHP4	ENST00000378169.7	c.*2132+31A>G		intron_variant, NMD_transcript_variant		1
NPHP4	ENST00000489180.6	c.*1042+31A>G		intron_variant, NMD_transcript_variant		2
NPHP4	ENST00000478423.6	n.2963+31A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32693 AN: 151922 Hom.: 3941 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.216

GnomAD3 exomes AF: 0.272 AC: 30953 AN: 113764 Hom.: 4706 AF XY: 0.280 AC XY: 16699 AN XY: 59684

Gnomad AFR exome AF: 0.0996

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.390

Gnomad SAS exome AF: 0.419

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.248 AC: 331310 AN: 1333984 Hom.: 43410 Cov.: 31 AF XY: 0.253 AC XY: 164742 AN XY: 650630

Gnomad4 AFR exome AF: 0.0990

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.231

Gnomad4 EAS exome AF: 0.425

Gnomad4 SAS exome AF: 0.417

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.215 AC: 32707 AN: 152040 Hom.: 3940 Cov.: 32 AF XY: 0.221 AC XY: 16439 AN XY: 74308

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.274

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.410

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.237

Gnomad4 OTH AF: 0.216

Alfa AF: 0.230 Hom.: 2939

Bravo AF: 0.209

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.24
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs905467; hg19: chr1-5934500; COSMIC: COSV65393891; COSMIC: COSV65393891;