NM_153240.5:c.*650_*651delAA

Variant names:

• chr3-132681258-CTT-C
• rs886058000
• NM_153240.5:c.*650_*651delAA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_153240.5(NPHP3):​c.*650_*651delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0889 in 105,186 control chromosomes in the GnomAD database, including 200 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.089 (200 hom., cov: 23)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: NPHP3 NM_153240.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.19
• Publications: 0 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 -9 ACMG points.

• BP6: Variant 3-132681258-CTT-C is Benign according to our data. Variant chr3-132681258-CTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343367.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

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.*650_*651delAA		3_prime_UTR	Exon 27 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3995+654_3995+655delAA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.*650_*651delAA		3_prime_UTR	Exon 27 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.635+654_635+655delAA		intron	N/A	ENSP00000488520.1	A0A0J9YXS1
	NPHP3	ENST00000971413.1		c.*650_*651delAA		splice_region	Exon 25 of 25	ENSP00000641472.1

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 9350 AN: 105104 Hom.: 200 Cov.: 23

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.0519

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.119

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.108

GnomAD4 exome AF: 0.0270 AC: 2 AN: 74 Hom.: 0 AF XY: 0.0370 AC XY: 2 AN XY: 54

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0152 AC: 1 AN: 66

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0889 AC: 9348 AN: 105112 Hom.: 200 Cov.: 23 AF XY: 0.0897 AC XY: 4386 AN XY: 48914

African (AFR) AF: 0.0267 AC: 736 AN: 27606

American (AMR) AF: 0.112 AC: 1134 AN: 10160

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 408 AN: 2766

East Asian (EAS) AF: 0.123 AC: 337 AN: 2736

South Asian (SAS) AF: 0.121 AC: 359 AN: 2968

European-Finnish (FIN) AF: 0.0995 AC: 417 AN: 4192

Middle Eastern (MID) AF: 0.118 AC: 21 AN: 178

European-Non Finnish (NFE) AF: 0.110 AC: 5749 AN: 52412

Other (OTH) AF: 0.107 AC: 152 AN: 1420

Alfa AF: 0.0210 Hom.: 8

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel-Gruber syndrome (1)
-	1	-	Nephronophthisis (1)
-	-	1	not provided (1)
-	1	-	Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886058000; hg19: chr3-132400102;