1-5877102-C-T

Position:

• chr1-5877102-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015102.5(NPHP4):​c.2808G>A​(p.Thr936=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,568,274 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 35)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: NPHP4 NM_015102.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0140

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-5877102-C-T is Benign according to our data. Variant chr1-5877102-C-T is described in ClinVar as [Benign]. Clinvar id is 240968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.014 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0114 (1729/152330) while in subpopulation AFR AF= 0.0397 (1649/41562). AF 95% confidence interval is 0.0381. There are 36 homozygotes in gnomad4. There are 829 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.2808G>A	p.Thr936=	synonymous_variant	20/30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.2808G>A	p.Thr936=	synonymous_variant	20/30	1	NM_015102.5	ENSP00000367398	P2

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1730 AN: 152212 Hom.: 37 Cov.: 35

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00333

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: 0.0000882

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00262 AC: 603 AN: 230186 Hom.: 16 AF XY: 0.00190 AC XY: 238 AN XY: 125138

Gnomad AFR exome AF: 0.0392

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.0000579

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000769

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.00120 AC: 1697 AN: 1415944 Hom.: 37 Cov.: 29 AF XY: 0.00100 AC XY: 697 AN XY: 697280

Gnomad4 AFR exome AF: 0.0443

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.0000403

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000245

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000231

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.0114 AC: 1729 AN: 152330 Hom.: 36 Cov.: 35 AF XY: 0.0111 AC XY: 829 AN XY: 74484

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.00326

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00427 Hom.: 9

Bravo AF: 0.0129

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 09, 2015	- -

Senior-Loken syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nephronophthisis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Nephronophthisis 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.61
DANN	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17028857; hg19: chr1-5937162; COSMIC: COSV100976813; COSMIC: COSV100976813;