1-5866447-T-C

Variant names:

• chr1-5866447-T-C
• rs555164
• NM_015102.5:c.3570A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015102.5(NPHP4):​c.3570A>G​(p.Glu1190Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,588,154 control chromosomes in the GnomAD database, including 131,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10239 hom., cov: 32)
  • Exomes 𝑓: 0.41 (121644 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.305
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-5866447-T-C is Benign according to our data. Variant chr1-5866447-T-C is described in ClinVar as Benign. ClinVar VariationId is 95683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.305 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.416 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.3570A>G	p.Glu1190Glu	synonymous	Exon 26 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.2034A>G	p.Glu678Glu	synonymous	Exon 22 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2031A>G	p.Glu677Glu	synonymous	Exon 23 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.3570A>G	p.Glu1190Glu	synonymous	Exon 26 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2471A>G		non_coding_transcript_exon	Exon 23 of 27	ENSP00000367411.3
	NPHP4	ENST00000460696.1	TSL:1	n.635A>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53741 AN: 151904 Hom.: 10237 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.369

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.362

GnomAD2 exomes AF: 0.393 AC: 87822 AN: 223688 AF XY: 0.398

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.256

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.422

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.408 AC: 585860 AN: 1436130 Hom.: 121644 Cov.: 30 AF XY: 0.409 AC XY: 291912 AN XY: 713438

African (AFR) AF: 0.199 AC: 6581 AN: 32988

American (AMR) AF: 0.369 AC: 15776 AN: 42778

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11892 AN: 25800

East Asian (EAS) AF: 0.266 AC: 10375 AN: 38972

South Asian (SAS) AF: 0.431 AC: 35931 AN: 83378

European-Finnish (FIN) AF: 0.426 AC: 22237 AN: 52222

Middle Eastern (MID) AF: 0.401 AC: 2293 AN: 5718

European-Non Finnish (NFE) AF: 0.417 AC: 456854 AN: 1094818

Other (OTH) AF: 0.402 AC: 23921 AN: 59456

GnomAD4 genome AF: 0.354 AC: 53764 AN: 152024 Hom.: 10239 Cov.: 32 AF XY: 0.356 AC XY: 26423 AN XY: 74290

African (AFR) AF: 0.209 AC: 8648 AN: 41470

American (AMR) AF: 0.369 AC: 5643 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1602 AN: 3472

East Asian (EAS) AF: 0.271 AC: 1400 AN: 5170

South Asian (SAS) AF: 0.430 AC: 2063 AN: 4800

European-Finnish (FIN) AF: 0.428 AC: 4517 AN: 10564

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28517 AN: 67954

Other (OTH) AF: 0.358 AC: 757 AN: 2112

Alfa AF: 0.404 Hom.: 16167

Bravo AF: 0.340

Asia WGS AF: 0.377 AC: 1310 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Nephronophthisis 4 (2)
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.2
DANN	Benign	0.45
PhyloP100		0.30
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: rs555164; hg19: chr1-5926507; COSMIC: COSV65394708; COSMIC: COSV65394708;