rs200104274

Variant names:

• chr1-5905312-T-C
• rs200104274
• NM_015102.5:c.1935A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_015102.5(NPHP4):​c.1935A>G​(p.Leu645Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,613,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.419
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 1-5905312-T-C is Benign according to our data. Variant chr1-5905312-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215885.
• BP7: Synonymous conserved (PhyloP=-0.419 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000453 (69/152340) while in subpopulation AFR AF = 0.00163 (68/41594). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.1935A>G	p.Leu645Leu	synonymous	Exon 15 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.399A>G	p.Leu133Leu	synonymous	Exon 11 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.396A>G	p.Leu132Leu	synonymous	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.1935A>G	p.Leu645Leu	synonymous	Exon 15 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*836A>G		non_coding_transcript_exon	Exon 12 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000466897.1	TSL:1	n.12A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000425745.1	H0YA08

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249308 AF XY: 0.0000961

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 51 AN: 1461182 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 726882

African (AFR) AF: 0.00122 AC: 41 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111394

Other (OTH) AF: 0.000133 AC: 8 AN: 60354

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74494

African (AFR) AF: 0.00163 AC: 68 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000491

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Nephronophthisis (1)
-	1	-	not provided (1)
-	-	1	NPHP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.8
DANN	Benign	0.54
PhyloP100		-0.42
Mutation Taster		=100/0	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: rs200104274; hg19: chr1-5965372;