chr1-5867109-G-A

Variant names:

• chr1-5867109-G-A
• rs113445782
• NM_015102.5:c.3479C>T

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.3479C>T​(p.Pro1160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,610,202 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1160P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.014 (185 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.22
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010002285).
• BP6: Variant 1-5867109-G-A is Benign according to our data. Variant chr1-5867109-G-A is described in ClinVar as Benign. ClinVar VariationId is 220304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0112 (1706/152224) while in subpopulation AMR AF = 0.0188 (288/15302). AF 95% confidence interval is 0.017. There are 21 homozygotes in GnomAd4. There are 766 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.3479C>T	p.Pro1160Leu	missense	Exon 25 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1943C>T	p.Pro648Leu	missense	Exon 21 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1940C>T	p.Pro647Leu	missense	Exon 22 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.3479C>T	p.Pro1160Leu	missense	Exon 25 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2380C>T		non_coding_transcript_exon	Exon 22 of 27	ENSP00000367411.3
	NPHP4	ENST00000460696.1	TSL:1	n.544C>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1707 AN: 152106 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0111 AC: 2684 AN: 242320 AF XY: 0.0116

Gnomad AFR exome AF: 0.00291

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0214

Gnomad EAS exome AF: 0.000682

Gnomad FIN exome AF: 0.00338

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0143 AC: 20897 AN: 1457978 Hom.: 185 Cov.: 30 AF XY: 0.0141 AC XY: 10255 AN XY: 724950

African (AFR) AF: 0.00260 AC: 87 AN: 33422

American (AMR) AF: 0.0142 AC: 627 AN: 44202

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 575 AN: 26070

East Asian (EAS) AF: 0.000556 AC: 22 AN: 39570

South Asian (SAS) AF: 0.00490 AC: 419 AN: 85464

European-Finnish (FIN) AF: 0.00416 AC: 221 AN: 53158

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5764

European-Non Finnish (NFE) AF: 0.0163 AC: 18042 AN: 1110082

Other (OTH) AF: 0.0140 AC: 841 AN: 60246

GnomAD4 genome AF: 0.0112 AC: 1706 AN: 152224 Hom.: 21 Cov.: 33 AF XY: 0.0103 AC XY: 766 AN XY: 74416

African (AFR) AF: 0.00371 AC: 154 AN: 41532

American (AMR) AF: 0.0188 AC: 288 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5174

South Asian (SAS) AF: 0.00437 AC: 21 AN: 4810

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0164 AC: 1115 AN: 68016

Other (OTH) AF: 0.0166 AC: 35 AN: 2114

Alfa AF: 0.0143 Hom.: 66

Bravo AF: 0.0129

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00273 AC: 11

ESP6500EA AF: 0.0180 AC: 150

ExAC AF: 0.0103 AC: 1250

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	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	0.099
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.36	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.56	P
Vest4		0.32
MPC		0.071
ClinPred		0.024	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.47
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs113445782; hg19: chr1-5927169; COSMIC: COSV100977184; COSMIC: COSV100977184;