rs375237454

Variant names:

• chr1-5864497-G-A
• rs375237454
• NM_015102.5:c.3837C>T

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.3837C>T​(p.Phe1279Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,589,260 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 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.720
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-5864497-G-A is Benign according to our data. Variant chr1-5864497-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167371.
• BP7: Synonymous conserved (PhyloP=-0.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000381 (58/152346) while in subpopulation AFR AF = 0.00123 (51/41588). AF 95% confidence interval is 0.000957. There are 0 homozygotes in GnomAd4. There are 34 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3837C>T	p.Phe1279Phe	synonymous	Exon 28 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.2301C>T	p.Phe767Phe	synonymous	Exon 24 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2298C>T	p.Phe766Phe	synonymous	Exon 25 of 27	NP_001278522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3837C>T	p.Phe1279Phe	synonymous	Exon 28 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2738C>T		non_coding_transcript_exon	Exon 25 of 27	ENSP00000367411.3
	NPHP4	ENST00000460696.1	TSL:1	n.2585C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000986 AC: 21 AN: 213030 AF XY: 0.0000776

Gnomad AFR exome AF: 0.00131

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000421

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 162 AN: 1436914 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 77 AN XY: 711820

African (AFR) AF: 0.00122 AC: 40 AN: 32850

American (AMR) AF: 0.0000483 AC: 2 AN: 41432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25526

East Asian (EAS) AF: 0.00 AC: 0 AN: 38660

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51440

Middle Eastern (MID) AF: 0.00351 AC: 20 AN: 5698

European-Non Finnish (NFE) AF: 0.0000810 AC: 89 AN: 1098810

Other (OTH) AF: 0.000152 AC: 9 AN: 59270

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.000456 AC XY: 34 AN XY: 74498

African (AFR) AF: 0.00123 AC: 51 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15312

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.000431

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.83
CADD	Benign	7.4
DANN	Benign	0.78
PhyloP100		-0.72
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs375237454; hg19: chr1-5924557; COSMIC: COSV65393837; COSMIC: COSV65393837;