chr1-5866443-G-A

Variant names:

• chr1-5866443-G-A
• rs139022622
• NM_015102.5:c.3574C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.3574C>T​(p.Arg1192Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,600,152 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1192Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.50
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06809828).
• BP6: Variant 1-5866443-G-A is Benign according to our data. Variant chr1-5866443-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 188389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00169 (257/152232) while in subpopulation NFE AF = 0.00297 (202/68010). AF 95% confidence interval is 0.00263. There are 0 homozygotes in GnomAd4. There are 119 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.3574C>T	p.Arg1192Trp	missense	Exon 26 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.2038C>T	p.Arg680Trp	missense	Exon 22 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2035C>T	p.Arg679Trp	missense	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.3574C>T	p.Arg1192Trp	missense	Exon 26 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*2475C>T		non_coding_transcript_exon	Exon 23 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000460696.1	TSL:1	n.639C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00181 AC: 412 AN: 227148 AF XY: 0.00170

Gnomad AFR exome AF: 0.000374

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.00284

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00204 AC: 2958 AN: 1447920 Hom.: 4 Cov.: 29 AF XY: 0.00203 AC XY: 1459 AN XY: 719278

African (AFR) AF: 0.000241 AC: 8 AN: 33190

American (AMR) AF: 0.00168 AC: 73 AN: 43414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39158

South Asian (SAS) AF: 0.0000239 AC: 2 AN: 83850

European-Finnish (FIN) AF: 0.00207 AC: 109 AN: 52544

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5752

European-Non Finnish (NFE) AF: 0.00241 AC: 2659 AN: 1104242

Other (OTH) AF: 0.00165 AC: 99 AN: 59864

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74440

African (AFR) AF: 0.000457 AC: 19 AN: 41532

American (AMR) AF: 0.000850 AC: 13 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68010

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00229 Hom.: 12

Bravo AF: 0.00162

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00103 AC: 4

ESP6500EA AF: 0.00231 AC: 19

ExAC AF: 0.00179 AC: 216

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Nephronophthisis (1)
-	-	1	not specified (1)
-	-	1	NPHP4-related disorder (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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.5
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.79
MPC		0.36
ClinPred		0.034	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.47
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs139022622; hg19: chr1-5926503; COSMIC: COSV104688987; COSMIC: COSV104688987;