2-110128565-G-A

Variant names:

• chr2-110128565-G-A
• rs3789735
• NM_001128178.3:c.1716+621C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001128178.3(NPHP1):​c.1716+621C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 153,516 control chromosomes in the GnomAD database, including 8,132 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.31 (8046 hom., cov: 32)
  • Exomes 𝑓: 0.30 (86 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.105
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.559 is higher than 0.05.

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.1716+621C>T		intron	N/A	NP_001121650.1
	NPHP1	NM_000272.5		c.1884+621C>T		intron	N/A	NP_000263.2
	NPHP1	NM_207181.4		c.1881+621C>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.1716+621C>T		intron	N/A	ENSP00000389879.3
	NPHP1	ENST00000316534.8	TSL:1	c.1884+621C>T		intron	N/A	ENSP00000313169.4
	NPHP1	ENST00000393272.7	TSL:1	c.1881+621C>T		intron	N/A	ENSP00000376953.3

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47448 AN: 151866 Hom.: 8023 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.498

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.315

GnomAD4 exome AF: 0.304 AC: 465 AN: 1532 Hom.: 86 Cov.: 0 AF XY: 0.314 AC XY: 258 AN XY: 822

African (AFR) AF: 1.00 AC: 4 AN: 4

American (AMR) AF: 0.283 AC: 65 AN: 230

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 3 AN: 10

East Asian (EAS) AF: 0.475 AC: 19 AN: 40

South Asian (SAS) AF: 0.536 AC: 30 AN: 56

European-Finnish (FIN) AF: 0.500 AC: 8 AN: 16

Middle Eastern (MID) AF: 0.333 AC: 2 AN: 6

European-Non Finnish (NFE) AF: 0.281 AC: 310 AN: 1102

Other (OTH) AF: 0.353 AC: 24 AN: 68

GnomAD4 genome AF: 0.313 AC: 47526 AN: 151984 Hom.: 8046 Cov.: 32 AF XY: 0.317 AC XY: 23539 AN XY: 74288

African (AFR) AF: 0.241 AC: 10013 AN: 41466

American (AMR) AF: 0.378 AC: 5769 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1090 AN: 3468

East Asian (EAS) AF: 0.576 AC: 2967 AN: 5152

South Asian (SAS) AF: 0.499 AC: 2394 AN: 4796

European-Finnish (FIN) AF: 0.224 AC: 2370 AN: 10560

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21825 AN: 67968

Other (OTH) AF: 0.316 AC: 666 AN: 2108

Alfa AF: 0.323 Hom.: 5107

Bravo AF: 0.317

Asia WGS AF: 0.501 AC: 1741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		-0.10
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: rs3789735; hg19: chr2-110886142;