rs571655

Variant names:

• chr1-5905395-C-T
• rs571655
• NM_015102.5:c.1852G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-5905395-C-T
• chr1-5905395-C-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.1852G>A​(p.Glu618Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0118 in 1,613,372 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (7 hom., cov: 33)
  • Exomes 𝑓: 0.012 (152 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 3.89
• Publications: 14 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=0.0073396564).
• BP6: Variant 1-5905395-C-T is Benign according to our data. Variant chr1-5905395-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240965.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 = 0.00997 (1518/152240) while in subpopulation NFE AF = 0.0144 (981/68012). AF 95% confidence interval is 0.0137. There are 7 homozygotes in GnomAd4. There are 723 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.1852G>A	p.Glu618Lys	missense	Exon 15 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.316G>A	p.Glu106Lys	missense	Exon 11 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.313G>A	p.Glu105Lys	missense	Exon 12 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.1852G>A	p.Glu618Lys	missense	Exon 15 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*753G>A		non_coding_transcript_exon	Exon 12 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.1849G>A		non_coding_transcript_exon	Exon 15 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.00997 AC: 1517 AN: 152122 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00309

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0104 AC: 2585 AN: 249266 AF XY: 0.0104

Gnomad AFR exome AF: 0.00258

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.0311

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0120 AC: 17540 AN: 1461132 Hom.: 152 Cov.: 32 AF XY: 0.0119 AC XY: 8680 AN XY: 726796

African (AFR) AF: 0.00370 AC: 124 AN: 33470

American (AMR) AF: 0.00613 AC: 274 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 804 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00308 AC: 266 AN: 86248

European-Finnish (FIN) AF: 0.00942 AC: 503 AN: 53402

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5766

European-Non Finnish (NFE) AF: 0.0131 AC: 14563 AN: 1111342

Other (OTH) AF: 0.0133 AC: 805 AN: 60360

GnomAD4 genome AF: 0.00997 AC: 1518 AN: 152240 Hom.: 7 Cov.: 33 AF XY: 0.00971 AC XY: 723 AN XY: 74444

African (AFR) AF: 0.00308 AC: 128 AN: 41532

American (AMR) AF: 0.00954 AC: 146 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4820

European-Finnish (FIN) AF: 0.00943 AC: 100 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0144 AC: 981 AN: 68012

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0135 Hom.: 52

Bravo AF: 0.00984

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00354 AC: 14

ESP6500EA AF: 0.0148 AC: 124

ExAC AF: 0.0103 AC: 1239

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0171

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0073	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.43
MPC		0.15
ClinPred		0.038	T
GERP RS		3.6
Varity_R		0.15
gMVP		0.48
Mutation Taster		=96/4	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: rs571655; hg19: chr1-5965455;