3-132722299-C-G

Variant names:

• chr3-132722299-C-G
• rs192633696
• NM_153240.5:c.57G>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_153240.5(NPHP3):​c.57G>C​(p.Thr19Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,580,942 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T19T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 31)
  • Exomes 𝑓: 0.018 (291 hom.)
• Consequence: NPHP3 NM_153240.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0270
• Publications: 5 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-AS1 (HGNC:24129): (NPHP3 antisense RNA 1)

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 3-132722299-C-G is Benign according to our data. Variant chr3-132722299-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.027 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (2105/152090) while in subpopulation NFE AF = 0.0202 (1374/67966). AF 95% confidence interval is 0.0193. There are 20 homozygotes in GnomAd4. There are 978 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153240.5. 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
	NPHP3	NM_153240.5	MANE Select	c.57G>C	p.Thr19Thr	synonymous	Exon 1 of 27	NP_694972.3
	NPHP3-AS1	NR_002811.2		n.550C>G		non_coding_transcript_exon	Exon 1 of 11
	NPHP3-ACAD11	NR_037804.1		n.161G>C		non_coding_transcript_exon	Exon 1 of 45

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.57G>C	p.Thr19Thr	synonymous	Exon 1 of 27	ENSP00000338766.5
	NPHP3	ENST00000383282.3	TSL:1	c.57G>C	p.Thr19Thr	synonymous	Exon 1 of 2	ENSP00000372769.2
	NPHP3-AS1	ENST00000489343.5	TSL:1	n.550C>G		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2108 AN: 151982 Hom.: 20 Cov.: 31

Gnomad AFR AF: 0.00403

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0147

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0158 AC: 3306 AN: 209862 AF XY: 0.0161

Gnomad AFR exome AF: 0.00317

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0261

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0145

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0178 AC: 25370 AN: 1428852 Hom.: 291 Cov.: 31 AF XY: 0.0177 AC XY: 12602 AN XY: 711228

African (AFR) AF: 0.00235 AC: 73 AN: 31072

American (AMR) AF: 0.0142 AC: 613 AN: 43036

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 647 AN: 25558

East Asian (EAS) AF: 0.00 AC: 0 AN: 37612

South Asian (SAS) AF: 0.0114 AC: 958 AN: 84224

European-Finnish (FIN) AF: 0.0133 AC: 510 AN: 38338

Middle Eastern (MID) AF: 0.0197 AC: 99 AN: 5024

European-Non Finnish (NFE) AF: 0.0194 AC: 21446 AN: 1104548

Other (OTH) AF: 0.0172 AC: 1024 AN: 59440

GnomAD4 genome AF: 0.0138 AC: 2105 AN: 152090 Hom.: 20 Cov.: 31 AF XY: 0.0132 AC XY: 978 AN XY: 74328

African (AFR) AF: 0.00402 AC: 167 AN: 41516

American (AMR) AF: 0.0143 AC: 218 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00953 AC: 46 AN: 4828

European-Finnish (FIN) AF: 0.0147 AC: 155 AN: 10564

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0202 AC: 1374 AN: 67966

Other (OTH) AF: 0.0176 AC: 37 AN: 2108

Alfa AF: 0.0118 Hom.: 6

Bravo AF: 0.0139

Asia WGS AF: 0.00551 AC: 19 AN: 3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 21, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 18, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Renal-hepatic-pancreatic dysplasia 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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.

Kidney disorder Benign:1

Jan 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NPHP3-related Meckel-like syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 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.

Nephronophthisis Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nephronophthisis 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.69
PhyloP100		-0.027
PromoterAI		-0.15	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs192633696; hg19: chr3-132441143;