rs113450177

Variant names:

• chr2-110165091-G-A
• rs113450177
• NM_001128178.3:c.689C>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_000272.5(NPHP1):​c.689C>T​(p.Ala230Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,368 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A230E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (26 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: NPHP1 NM_000272.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.18
• Publications: 5 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 (MetaRNN=0.001884073).
• BP6: Variant 2-110165091-G-A is Benign according to our data. Variant chr2-110165091-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1565/151944) while in subpopulation AFR AF = 0.0363 (1503/41420). AF 95% confidence interval is 0.0348. There are 26 homozygotes in GnomAd4. There are 736 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000272.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	NM_001128178.3	MANE Select	c.689C>T	p.Ala230Val	missense	Exon 7 of 20	NP_001121650.1
	NPHP1	NM_000272.5		c.689C>T	p.Ala230Val	missense	Exon 7 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.689C>T	p.Ala230Val	missense	Exon 7 of 20	NP_997064.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.689C>T	p.Ala230Val	missense	Exon 7 of 20	ENSP00000389879.3
	NPHP1	ENST00000316534.8	TSL:1	c.689C>T	p.Ala230Val	missense	Exon 7 of 20	ENSP00000313169.4
	NPHP1	ENST00000393272.7	TSL:1	c.689C>T	p.Ala230Val	missense	Exon 7 of 20	ENSP00000376953.3

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1560 AN: 151826 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00273 AC: 686 AN: 251216 AF XY: 0.00215

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00110 AC: 1604 AN: 1461424 Hom.: 35 Cov.: 31 AF XY: 0.000963 AC XY: 700 AN XY: 727046

African (AFR) AF: 0.0383 AC: 1278 AN: 33404

American (AMR) AF: 0.00221 AC: 99 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86242

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53392

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000765 AC: 85 AN: 1111720

Other (OTH) AF: 0.00212 AC: 128 AN: 60382

GnomAD4 genome AF: 0.0103 AC: 1565 AN: 151944 Hom.: 26 Cov.: 32 AF XY: 0.00991 AC XY: 736 AN XY: 74260

African (AFR) AF: 0.0363 AC: 1503 AN: 41420

American (AMR) AF: 0.00295 AC: 45 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10534

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67968

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00393 Hom.: 17

Bravo AF: 0.0126

ESP6500AA AF: 0.0336 AC: 148

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00355 AC: 431

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Joubert syndrome with renal defect (1)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 1 (1)
-	-	1	not specified (1)
-	-	1	Senior-Loken syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.3
DANN	Benign	0.34
DEOGEN2	Benign	0.057	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N
PhyloP100		1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.049
Sift	Benign	0.83	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.028
MVP		0.69
MPC		0.077
ClinPred		0.0020	T
GERP RS		2.6
Varity_R		0.025
gMVP		0.089
Mutation Taster		=96/4	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: rs113450177; hg19: chr2-110922668; COSMIC: COSV57209838;