3-132715098-T-G

Variant names:

• chr3-132715098-T-G
• rs149565564
• NM_153240.5:c.944A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153240.5(NPHP3):​c.944A>C​(p.Asp315Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,459,132 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D315V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24653122).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.944A>C	p.Asp315Ala	missense	Exon 5 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.1048A>C		non_coding_transcript_exon	Exon 5 of 45

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.944A>C	p.Asp315Ala	missense	Exon 5 of 27	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.650A>C		non_coding_transcript_exon	Exon 5 of 25	ENSP00000419907.1
	NPHP3	ENST00000469232.5	TSL:2	n.*387A>C		non_coding_transcript_exon	Exon 6 of 13	ENSP00000418664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251288 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459132 Hom.: 0 Cov.: 28 AF XY: 0.00000275 AC XY: 2 AN XY: 726080

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1109702

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.044	D
Sift4G	Benign	0.065	T
Polyphen		0.016	B
Vest4		0.37
MutPred		0.28		Loss of ubiquitination at K319 (P = 0.0433)
MVP		0.92
MPC		0.24
ClinPred		0.42	T
GERP RS		6.2
Varity_R		0.14
gMVP		0.69
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149565564; hg19: chr3-132433942;