3-132688789-C-T

Variant names:

• chr3-132688789-C-T
• rs150867534
• NM_153240.5:c.2986G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_153240.5(NPHP3):​c.2986G>A​(p.Val996Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,614,050 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 3.20
• Publications: 4 publications found

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:48351): (NPHP3-ACAD11 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring NPHP3 (nephronophthisis 3, adolescent) and ACAD11 (acyl-CoA dehydrogenase family, member 11) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07308802).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000225 (329/1461856) while in subpopulation EAS AF = 0.00521 (207/39698). AF 95% confidence interval is 0.00463. There are 2 homozygotes in GnomAdExome4. There are 171 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.2986G>A	p.Val996Met	missense_variant	Exon 21 of 27	ENST00000337331.10	NP_694972.3
NPHP3-ACAD11	NR_037804.1	n.2992G>A		non_coding_transcript_exon_variant	Exon 20 of 45

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.2986G>A	p.Val996Met	missense_variant	Exon 21 of 27	1	NM_153240.5	ENSP00000338766.5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000135 AC: 34 AN: 251124 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000225 AC: 329 AN: 1461856 Hom.: 2 Cov.: 33 AF XY: 0.000235 AC XY: 171 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00521 AC: 207 AN: 39698

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111976

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74414

African (AFR) AF: 0.0000963 AC: 4 AN: 41530

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000981 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 21, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 22, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal-hepatic-pancreatic dysplasia 1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Inborn genetic diseases Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2986G>A (p.V996M) alteration is located in exon 21 (coding exon 21) of the NPHP3 gene. This alteration results from a G to A substitution at nucleotide position 2986, causing the valine (V) at amino acid position 996 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 Uncertain:1

Jan 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NPHP3-related Meckel-like syndrome Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nephronophthisis Uncertain:1

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 996 of the NPHP3 protein (p.Val996Met). This variant is present in population databases (rs150867534, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with NPHP3-related conditions. ClinVar contains an entry for this variant (Variation ID: 531625). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHP3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Nephronophthisis 3 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.026
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.073	T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	0.12	N
PhyloP100		3.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.31
Sift	Benign	0.25	T
Sift4G	Benign	0.097	T
Polyphen		0.54	P
Vest4		0.29
MVP		0.91
MPC		0.31
ClinPred		0.040	T
GERP RS		5.6
Varity_R		0.087
gMVP		0.50
Mutation Taster		=82/18	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: rs150867534; hg19: chr3-132407633; COSMIC: COSV58628807; COSMIC: COSV58628807;