NM_001128178.3:c.1529+19C>T

Variant names:

• chr2-110143523-G-A
• rs112090979
• NM_001128178.3:c.1529+19C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001128178.3(NPHP1):​c.1529+19C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,554,506 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (22 hom., cov: 32)
  • Exomes 𝑓: 0.013 (183 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0740
• Publications: 2 publications found

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• Bardet-Biedl syndrome

  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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-110143523-G-A is Benign according to our data. Variant chr2-110143523-G-A is described in ClinVar as Benign. ClinVar VariationId is 255708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0107 (1622/152258) while in subpopulation NFE AF = 0.0156 (1059/68016). AF 95% confidence interval is 0.0148. There are 22 homozygotes in GnomAd4. There are 812 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. 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
	NPHP1	NM_001128178.3	MANE Select	c.1529+19C>T		intron	N/A	NP_001121650.1
	NPHP1	NM_000272.5		c.1697+19C>T		intron	N/A	NP_000263.2
	NPHP1	NM_207181.4		c.1694+19C>T		intron	N/A	NP_997064.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.1529+19C>T		intron	N/A	ENSP00000389879.3
	NPHP1	ENST00000316534.8	TSL:1	c.1697+19C>T		intron	N/A	ENSP00000313169.4
	NPHP1	ENST00000393272.7	TSL:1	c.1694+19C>T		intron	N/A	ENSP00000376953.3

Frequencies

GnomAD3 genomes AF: 0.0107 AC: 1622 AN: 152140 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0107 AC: 2696 AN: 251228 AF XY: 0.0107

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00602

Gnomad ASJ exome AF: 0.0175

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.0134 AC: 18796 AN: 1402248 Hom.: 183 Cov.: 24 AF XY: 0.0131 AC XY: 9176 AN XY: 701286

African (AFR) AF: 0.00263 AC: 85 AN: 32322

American (AMR) AF: 0.00656 AC: 293 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 510 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39440

South Asian (SAS) AF: 0.000963 AC: 82 AN: 85116

European-Finnish (FIN) AF: 0.0161 AC: 857 AN: 53364

Middle Eastern (MID) AF: 0.00879 AC: 50 AN: 5686

European-Non Finnish (NFE) AF: 0.0154 AC: 16252 AN: 1057582

Other (OTH) AF: 0.0114 AC: 667 AN: 58314

GnomAD4 genome AF: 0.0107 AC: 1622 AN: 152258 Hom.: 22 Cov.: 32 AF XY: 0.0109 AC XY: 812 AN XY: 74442

African (AFR) AF: 0.00257 AC: 107 AN: 41554

American (AMR) AF: 0.0112 AC: 171 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.0173 AC: 183 AN: 10600

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0156 AC: 1059 AN: 68016

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0140 Hom.: 27

Bravo AF: 0.00946

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 05, 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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.4
DANN	Benign	0.38
PhyloP100		0.074
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: rs112090979; hg19: chr2-110901100;