NM_153240.5:c.450G>A

Variant names:

• chr3-132719774-C-T
• rs78527322
• NM_153240.5:c.450G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_153240.5(NPHP3):​c.450G>A​(p.Ala150Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,602,544 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (32 hom.)
• Consequence: NPHP3 NM_153240.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.224
• 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 3-132719774-C-T is Benign according to our data. Variant chr3-132719774-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.224 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0086 (1306/151946) while in subpopulation AFR AF = 0.027 (1120/41460). AF 95% confidence interval is 0.0257. There are 16 homozygotes in GnomAd4. There are 617 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.450G>A	p.Ala150Ala	synonymous	Exon 2 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.554G>A		non_coding_transcript_exon	Exon 2 of 45

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.450G>A	p.Ala150Ala	synonymous	Exon 2 of 27	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.156G>A		non_coding_transcript_exon	Exon 2 of 25	ENSP00000419907.1
	NPHP3	ENST00000469232.5	TSL:2	n.102G>A		non_coding_transcript_exon	Exon 2 of 13	ENSP00000418664.1

Frequencies

GnomAD3 genomes AF: 0.00860 AC: 1305 AN: 151830 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0271

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000956

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00338 AC: 846 AN: 250054 AF XY: 0.00285

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00182 AC: 2647 AN: 1450598 Hom.: 32 Cov.: 28 AF XY: 0.00177 AC XY: 1281 AN XY: 721704

African (AFR) AF: 0.0304 AC: 1013 AN: 33310

American (AMR) AF: 0.00388 AC: 172 AN: 44354

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 81 AN: 25820

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00180 AC: 152 AN: 84530

European-Finnish (FIN) AF: 0.000530 AC: 28 AN: 52832

Middle Eastern (MID) AF: 0.0110 AC: 63 AN: 5716

European-Non Finnish (NFE) AF: 0.000868 AC: 959 AN: 1104850

Other (OTH) AF: 0.00299 AC: 179 AN: 59816

GnomAD4 genome AF: 0.00860 AC: 1306 AN: 151946 Hom.: 16 Cov.: 32 AF XY: 0.00831 AC XY: 617 AN XY: 74288

African (AFR) AF: 0.0270 AC: 1120 AN: 41460

American (AMR) AF: 0.00523 AC: 80 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0000956 AC: 1 AN: 10462

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 67958

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00447 Hom.: 5

Bravo AF: 0.0102

Asia WGS AF: 0.00434 AC: 15 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (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
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.81
PhyloP100		0.22
Mutation Taster		=88/12	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: rs78527322; hg19: chr3-132438618;