NM_153240.5:c.3941G>C

Variant names:

• chr3-132681962-C-G
• rs75316802
• NM_153240.5:c.3941G>C

Variant summary

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

The NM_153240.5(NPHP3):​c.3941G>C​(p.Ser1314Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00117 in 1,614,114 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (14 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.87
• 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-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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055725873).
• BP6: Variant 3-132681962-C-G is Benign according to our data. Variant chr3-132681962-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 188351.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 = 0.00613 (934/152296) while in subpopulation AFR AF = 0.021 (874/41558). AF 95% confidence interval is 0.0199. There are 7 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.3941G>C	p.Ser1314Thr	missense	Exon 27 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3947G>C		non_coding_transcript_exon	Exon 26 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3941G>C	p.Ser1314Thr	missense	Exon 27 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.587G>C	p.Ser196Thr	missense	Exon 4 of 5	ENSP00000488520.1	A0A0J9YXS1
	NPHP3	ENST00000971413.1		c.3740G>C	p.Ser1247Thr	missense	Exon 25 of 25	ENSP00000641472.1

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 934 AN: 152178 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00719

GnomAD2 exomes AF: 0.00156 AC: 392 AN: 251352 AF XY: 0.00114

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000651 AC: 952 AN: 1461818 Hom.: 14 Cov.: 31 AF XY: 0.000510 AC XY: 371 AN XY: 727210

African (AFR) AF: 0.0223 AC: 746 AN: 33478

American (AMR) AF: 0.00161 AC: 72 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111972

Other (OTH) AF: 0.00156 AC: 94 AN: 60394

GnomAD4 genome AF: 0.00613 AC: 934 AN: 152296 Hom.: 7 Cov.: 32 AF XY: 0.00595 AC XY: 443 AN XY: 74472

African (AFR) AF: 0.0210 AC: 874 AN: 41558

American (AMR) AF: 0.00255 AC: 39 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.00689

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00180 AC: 218

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	not specified (3)
-	-	2	Renal-hepatic-pancreatic dysplasia 1 (2)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (1)
-	-	1	Nephronophthisis 3;C2673885:NPHP3-related Meckel-like syndrome;C3715199:Renal-hepatic-pancreatic dysplasia 1 (1)
-	-	1	NPHP3-related Meckel-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.067
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.30
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.0080	B
Vest4		0.37
MVP		0.82
MPC		0.24
ClinPred		0.029	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.54
Mutation Taster		=87/13	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: rs75316802; hg19: chr3-132400806;