rs34391943

Positions:

• chr3-132684574-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153240.5(NPHP3):​c.3550G>A​(p.Ala1184Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00877 in 1,613,890 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1184V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0075 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (87 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 6.14

Genes affected

NPHP3 (HGNC:7907): (nephrocystin 3) This gene encodes a protein containing a coiled-coil (CC) domain, a tubulin-tyrosine ligase (TTL) domain, and a tetratrico peptide repeat (TPR) domain. The encoded protein interacts with nephrocystin, it is required for normal ciliary development, and it functions in renal tubular development. Mutations in this gene are associated with nephronophthisis type 3, and also with renal-hepatic-pancreatic dysplasia, and Meckel syndrome type 7. Naturally occurring read-through transcripts exist between this gene and the downstream ACAD11 (acyl-CoA dehydrogenase family, member 11) gene. [provided by RefSeq, Feb 2011]

NPHP3-ACAD11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011167735).
• BP6: Variant 3-132684574-C-T is Benign according to our data. Variant chr3-132684574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=6, Uncertain_significance=2}. Variant chr3-132684574-C-T is described in Lovd as [Likely_benign]. Variant chr3-132684574-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00749 (1140/152260) while in subpopulation NFE AF= 0.0113 (770/68002). AF 95% confidence interval is 0.0107. There are 12 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NPHP3	NM_153240.5	c.3550G>A	p.Ala1184Thr	missense_variant	24/27	ENST00000337331.10
NPHP3-ACAD11	NR_037804.1	n.3556G>A		non_coding_transcript_exon_variant	23/45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NPHP3	ENST00000337331.10	c.3550G>A	p.Ala1184Thr	missense_variant	24/27	1	NM_153240.5	P1

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1140 AN: 152142 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00823 AC: 2065 AN: 250872 Hom.: 12 AF XY: 0.00868 AC XY: 1178 AN XY: 135662

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00983

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.00890 AC: 13008 AN: 1461630 Hom.: 87 Cov.: 31 AF XY: 0.00924 AC XY: 6721 AN XY: 727122

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.00911

Gnomad4 OTH exome AF: 0.00942

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152260 Hom.: 12 Cov.: 32 AF XY: 0.00767 AC XY: 571 AN XY: 74460

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0105

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.0104 Hom.: 16

Bravo AF: 0.00611

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00863 AC: 1048

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 26, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NPHP3: BS1, BS2 -

NPHP3-related Meckel-like syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Bardet-Biedl syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Jun 02, 2023

- -

Renal-hepatic-pancreatic dysplasia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Invitae

Jan 31, 2024

- -

Nephronophthisis 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.94
MVP		0.91
MPC		0.72
ClinPred		0.091	T
GERP RS		4.7
Varity_R		0.74
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs34391943; hg19: chr3-132403418;