NM_153240.5:c.3756C>G

Variant names:

• chr3-132682759-G-C
• rs143451766
• NM_153240.5:c.3756C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_153240.5(NPHP3):​c.3756C>G​(p.Ser1252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000911 in 1,613,506 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (1 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 2.57
• Publications: 6 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2561572).
• BP6: Variant 3-132682759-G-C is Benign according to our data. Variant chr3-132682759-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195996.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000637 (97/152168) while in subpopulation NFE AF = 0.00116 (79/68010). AF 95% confidence interval is 0.000955. There are 0 homozygotes in GnomAd4. There are 49 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.3756C>G	p.Ser1252Arg	missense	Exon 26 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3762C>G		non_coding_transcript_exon	Exon 25 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3756C>G	p.Ser1252Arg	missense	Exon 26 of 27	ENSP00000338766.5
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.402C>G	p.Ser134Arg	missense	Exon 3 of 5	ENSP00000488520.1
	NPHP3	ENST00000971413.1		c.3555C>G	p.Ser1185Arg	missense	Exon 24 of 25	ENSP00000641472.1

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 97 AN: 152050 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000696 AC: 175 AN: 251270 AF XY: 0.000663

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000940 AC: 1373 AN: 1461338 Hom.: 1 Cov.: 30 AF XY: 0.000904 AC XY: 657 AN XY: 727002

African (AFR) AF: 0.000119 AC: 4 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86244

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00114 AC: 1270 AN: 1111548

Other (OTH) AF: 0.000414 AC: 25 AN: 60384

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000659 AC XY: 49 AN XY: 74382

African (AFR) AF: 0.000241 AC: 10 AN: 41508

American (AMR) AF: 0.000262 AC: 4 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 68010

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000676

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000749 AC: 91

EpiCase AF: 0.00147

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	-	1	Nephronophthisis (1)
-	1	-	Nephronophthisis 3 (1)
-	1	-	NPHP3-related disorder (1)
-	1	-	NPHP3-related Meckel-like syndrome (1)
-	1	-	Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.87	L
PhyloP100		2.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.58		Gain of glycosylation at Y1249 (P = 0.0129)
MVP		0.85
MPC		0.77
ClinPred		0.19	T
GERP RS		4.4
Varity_R		0.60
gMVP		0.76
Mutation Taster		=62/38	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: rs143451766; hg19: chr3-132401603; COSMIC: COSV99393504; COSMIC: COSV99393504;