chr2-110201449-G-T

Variant names:

• chr2-110201449-G-T
• rs33958626
• NM_001128178.3:c.115C>A

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.115C>A​(p.Pro39Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0333 in 1,608,126 control chromosomes in the GnomAD database, including 1,199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P39P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.027 (91 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1108 hom.)
• Consequence: NPHP1 NM_001128178.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.109
• Publications: 11 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=0.0015397668).
• BP6: Variant 2-110201449-G-T is Benign according to our data. Variant chr2-110201449-G-T is described in ClinVar as Benign. ClinVar VariationId is 129813.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 = 0.0266 (4050/152172) while in subpopulation NFE AF = 0.0395 (2685/68002). AF 95% confidence interval is 0.0382. There are 91 homozygotes in GnomAd4. There are 1965 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 91 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	NM_001128178.3	MANE Select	c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	NP_000263.2
	NPHP1	NM_207181.4		c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	NP_997064.2	O15259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.115C>A	p.Pro39Thr	missense	Exon 2 of 20	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4050 AN: 152054 Hom.: 91 Cov.: 33

Gnomad AFR AF: 0.00632

Gnomad AMI AF: 0.0341

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0513

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0270 AC: 6715 AN: 249006 AF XY: 0.0267

Gnomad AFR exome AF: 0.00588

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0190

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0512

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0340 AC: 49515 AN: 1455954 Hom.: 1108 Cov.: 29 AF XY: 0.0334 AC XY: 24178 AN XY: 724440

African (AFR) AF: 0.00526 AC: 176 AN: 33434

American (AMR) AF: 0.0195 AC: 871 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 488 AN: 26034

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39636

South Asian (SAS) AF: 0.00531 AC: 457 AN: 85998

European-Finnish (FIN) AF: 0.0508 AC: 2674 AN: 52596

Middle Eastern (MID) AF: 0.0387 AC: 217 AN: 5608

European-Non Finnish (NFE) AF: 0.0387 AC: 42890 AN: 1107806

Other (OTH) AF: 0.0289 AC: 1739 AN: 60196

GnomAD4 genome AF: 0.0266 AC: 4050 AN: 152172 Hom.: 91 Cov.: 33 AF XY: 0.0264 AC XY: 1965 AN XY: 74384

African (AFR) AF: 0.00631 AC: 262 AN: 41548

American (AMR) AF: 0.0254 AC: 388 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3470

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

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4824

European-Finnish (FIN) AF: 0.0513 AC: 542 AN: 10558

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0395 AC: 2685 AN: 68002

Other (OTH) AF: 0.0237 AC: 50 AN: 2110

Alfa AF: 0.0340 Hom.: 253

Bravo AF: 0.0246

TwinsUK AF: 0.0467 AC: 173

ALSPAC AF: 0.0355 AC: 137

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0267 AC: 3247

Asia WGS AF: 0.00404 AC: 14 AN: 3476

EpiCase AF: 0.0386

EpiControl AF: 0.0385

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Joubert syndrome with renal defect (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 1 (1)
-	-	1	Senior-Loken syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.83
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.11
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.059
Sift	Benign	0.089	T
Sift4G	Benign	0.11	T
Polyphen		0.0040	B
Vest4		0.088
MPC		0.091
ClinPred		0.010	T
GERP RS		0.48
PromoterAI		0.00040	Neutral
Varity_R		0.062
gMVP		0.11
Mutation Taster		=95/5	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: rs33958626; hg19: chr2-110959026;