rs114545322

Variant names:

• chr1-5877186-C-T
• rs114545322
• NM_015102.5:c.2724G>A

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.2724G>A​(p.Ser908Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,603,148 control chromosomes in the GnomAD database, including 369 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (195 hom., cov: 35)
  • Exomes 𝑓: 0.0031 (174 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.892
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 1-5877186-C-T is Benign according to our data. Variant chr1-5877186-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.892 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0943 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.2724G>A	p.Ser908Ser	synonymous	Exon 20 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1188G>A	p.Ser396Ser	synonymous	Exon 16 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1185G>A	p.Ser395Ser	synonymous	Exon 17 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.2724G>A	p.Ser908Ser	synonymous	Exon 20 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*1625G>A		non_coding_transcript_exon	Exon 17 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*272G>A		non_coding_transcript_exon	Exon 21 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4233 AN: 152246 Hom.: 194 Cov.: 35

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00671 AC: 1544 AN: 230026 AF XY: 0.00528

Gnomad AFR exome AF: 0.0972

Gnomad AMR exome AF: 0.00501

Gnomad ASJ exome AF: 0.000937

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000359

Gnomad OTH exome AF: 0.00493

GnomAD4 exome AF: 0.00305 AC: 4431 AN: 1450782 Hom.: 174 Cov.: 35 AF XY: 0.00263 AC XY: 1894 AN XY: 720486

African (AFR) AF: 0.0999 AC: 3325 AN: 33282

American (AMR) AF: 0.00584 AC: 255 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.00104 AC: 27 AN: 25884

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39208

South Asian (SAS) AF: 0.000178 AC: 15 AN: 84444

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52408

Middle Eastern (MID) AF: 0.00384 AC: 22 AN: 5734

European-Non Finnish (NFE) AF: 0.000388 AC: 429 AN: 1106296

Other (OTH) AF: 0.00596 AC: 357 AN: 59890

GnomAD4 genome AF: 0.0279 AC: 4246 AN: 152366 Hom.: 195 Cov.: 35 AF XY: 0.0272 AC XY: 2027 AN XY: 74514

African (AFR) AF: 0.0968 AC: 4022 AN: 41568

American (AMR) AF: 0.00921 AC: 141 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68040

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0137 Hom.: 50

Bravo AF: 0.0325

Asia WGS AF: 0.00462 AC: 16 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	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 4 (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
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.0
DANN	Benign	0.60
PhyloP100		-0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs114545322; hg19: chr1-5937246;