chr1-5982874-G-A

Variant names:

• chr1-5982874-G-A
• rs806104
• NM_015102.5:c.135+3281C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015102.5(NPHP4):​c.135+3281C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 152,050 control chromosomes in the GnomAD database, including 28,344 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (28344 hom., cov: 33)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.74 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.135+3281C>T		intron	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.-1088+9370C>T		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.-1095+3281C>T		intron	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.135+3281C>T		intron	N/A	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.135+3281C>T		intron	N/A	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.135+3281C>T		intron	N/A	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92504 AN: 151932 Hom.: 28333 Cov.: 33

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.681

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.614

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.609 AC: 92551 AN: 152050 Hom.: 28344 Cov.: 33 AF XY: 0.611 AC XY: 45413 AN XY: 74326

African (AFR) AF: 0.520 AC: 21543 AN: 41438

American (AMR) AF: 0.616 AC: 9410 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2222 AN: 3470

East Asian (EAS) AF: 0.760 AC: 3938 AN: 5182

South Asian (SAS) AF: 0.628 AC: 3026 AN: 4818

European-Finnish (FIN) AF: 0.681 AC: 7196 AN: 10560

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.636 AC: 43225 AN: 67992

Other (OTH) AF: 0.617 AC: 1300 AN: 2108

Alfa AF: 0.612 Hom.: 13208

Bravo AF: 0.601

Asia WGS AF: 0.626 AC: 2180 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.25
DANN	Benign	0.78
PhyloP100		-0.49
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: rs806104; hg19: chr1-6042934; COSMIC: COSV65394043;