3-132697362-C-T

Variant names:

• chr3-132697362-C-T
• rs77533254
• NM_153240.5:c.1986G>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.1986G>A​(p.Arg662Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,593,446 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (48 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: NPHP3 NM_153240.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.7586
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.70
• 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-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=-0.25).
• BP6: Variant 3-132697362-C-T is Benign according to our data. Variant chr3-132697362-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0139 (2109/152214) while in subpopulation AFR AF = 0.0482 (2002/41508). AF 95% confidence interval is 0.0465. There are 48 homozygotes in GnomAd4. There are 972 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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.1986G>A	p.Arg662Arg	splice_region synonymous	Exon 14 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.1992G>A		splice_region non_coding_transcript_exon	Exon 13 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.1986G>A	p.Arg662Arg	splice_region synonymous	Exon 14 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.1888-549G>A		intron	N/A	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.1887+2556G>A		intron	N/A	ENSP00000641471.1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2104 AN: 152096 Hom.: 47 Cov.: 33

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

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: 0.000132

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00336 AC: 835 AN: 248506 AF XY: 0.00236

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00128 AC: 1842 AN: 1441232 Hom.: 37 Cov.: 27 AF XY: 0.00108 AC XY: 773 AN XY: 718470

African (AFR) AF: 0.0463 AC: 1530 AN: 33022

American (AMR) AF: 0.00264 AC: 118 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51278

Middle Eastern (MID) AF: 0.000900 AC: 5 AN: 5558

European-Non Finnish (NFE) AF: 0.0000329 AC: 36 AN: 1095820

Other (OTH) AF: 0.00253 AC: 151 AN: 59746

GnomAD4 genome AF: 0.0139 AC: 2109 AN: 152214 Hom.: 48 Cov.: 33 AF XY: 0.0131 AC XY: 972 AN XY: 74426

African (AFR) AF: 0.0482 AC: 2002 AN: 41508

American (AMR) AF: 0.00490 AC: 75 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68010

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00431 Hom.: 21

Bravo AF: 0.0150

Asia WGS AF: 0.00174 AC: 6 AN: 3466

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	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
AlphaMissense	Benign	0.16
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.98
PhyloP100		2.7
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.060		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: rs77533254; hg19: chr3-132416206;