3-132722169-C-T

Variant names:

• chr3-132722169-C-T
• rs753458157
• NM_153240.5:c.187G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_153240.5(NPHP3):​c.187G>A​(p.Gly63Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,563,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G63E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 1 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-AS1 (HGNC:24129): (NPHP3 antisense RNA 1)

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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27766684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP3	NM_153240.5	c.187G>A	p.Gly63Arg	missense_variant	Exon 1 of 27	ENST00000337331.10	NP_694972.3
NPHP3-AS1	NR_002811.2	n.420C>T		non_coding_transcript_exon_variant	Exon 1 of 11
NPHP3-ACAD11	NR_037804.1	n.291G>A		non_coding_transcript_exon_variant	Exon 1 of 45
NPHP3-AS1	NR_152743.1	n.420C>T		non_coding_transcript_exon_variant	Exon 1 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP3	ENST00000337331.10	c.187G>A	p.Gly63Arg	missense_variant	Exon 1 of 27	1	NM_153240.5	ENSP00000338766.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000113 AC: 2 AN: 176792 AF XY: 0.0000100

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 30 AN: 1411324 Hom.: 0 Cov.: 31 AF XY: 0.0000214 AC XY: 15 AN XY: 700702

African (AFR) AF: 0.00 AC: 0 AN: 30872

American (AMR) AF: 0.00 AC: 0 AN: 39824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24750

East Asian (EAS) AF: 0.00 AC: 0 AN: 36226

South Asian (SAS) AF: 0.00 AC: 0 AN: 81984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.0000274 AC: 30 AN: 1094532

Other (OTH) AF: 0.00 AC: 0 AN: 58606

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000174 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.20	N;N
PhyloP100		4.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.23
Sift	Benign	0.069	T;T
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.056	B;.
Vest4		0.29
MutPred		0.43		Gain of MoRF binding (P = 0.0206);Gain of MoRF binding (P = 0.0206);
MVP		0.80
MPC		0.23
ClinPred		0.23	T
GERP RS		0.69
PromoterAI		-0.064	Neutral
Varity_R		0.068
gMVP		0.12
Mutation Taster		=98/2	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: rs753458157; hg19: chr3-132441013;