1-5905690-G-C

Variant names:

• chr1-5905690-G-C
• rs113413307
• NM_015102.5:c.1705C>G

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.1705C>G​(p.Gln569Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000775 in 1,613,932 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (5 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.90
• Publications: 5 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 (MetaRNN=0.008204877).
• BP6: Variant 1-5905690-G-C is Benign according to our data. Variant chr1-5905690-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235419.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 = 0.00415 (633/152366) while in subpopulation AFR AF = 0.0144 (599/41584). AF 95% confidence interval is 0.0134. There are 5 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.1705C>G	p.Gln569Glu	missense	Exon 14 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.169C>G	p.Gln57Glu	missense	Exon 10 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.166C>G	p.Gln56Glu	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.1705C>G	p.Gln569Glu	missense	Exon 14 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*606C>G		non_coding_transcript_exon	Exon 11 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.1702C>G		non_coding_transcript_exon	Exon 14 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 621 AN: 152248 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00101 AC: 252 AN: 248836 AF XY: 0.000748

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.000423 AC: 618 AN: 1461566 Hom.: 5 Cov.: 32 AF XY: 0.000378 AC XY: 275 AN XY: 727056

African (AFR) AF: 0.0135 AC: 451 AN: 33476

American (AMR) AF: 0.000760 AC: 34 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111814

Other (OTH) AF: 0.00177 AC: 107 AN: 60366

GnomAD4 genome AF: 0.00415 AC: 633 AN: 152366 Hom.: 5 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74510

African (AFR) AF: 0.0144 AC: 599 AN: 41584

American (AMR) AF: 0.00170 AC: 26 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00127 Hom.: 1

Bravo AF: 0.00454

ESP6500AA AF: 0.0128 AC: 52

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00131 AC: 159

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 4 (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0082	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.9
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.31
Sift	Benign	0.33	T
Sift4G	Uncertain	0.035	D
Polyphen		0.60	P
Vest4		0.24
MVP		0.93
MPC		0.19
ClinPred		0.026	T
GERP RS		5.4
Varity_R		0.15
gMVP		0.45
Mutation Taster		=98/2	polymorphism

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: rs113413307; hg19: chr1-5965750;