NM_153240.5:c.*651dupA

Variant names:

• chr3-132681258-C-CT
• rs886058000
• NM_153240.5:c.*651dupA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_153240.5(NPHP3):​c.*651dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 105,608 control chromosomes in the GnomAD database, including 49 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (49 hom., cov: 23)
  • Exomes 𝑓: 0.027 (0 hom.)
• Consequence: NPHP3 NM_153240.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter 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 -10 ACMG points.

• BP6: Variant 3-132681258-C-CT is Benign according to our data. Variant chr3-132681258-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1264737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0517 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.*651dupA		3_prime_UTR	Exon 27 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3995+655dupA		intron	N/A

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 2512 AN: 105526 Hom.: 48 Cov.: 23

Gnomad AFR AF: 0.0540

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00969

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.00603

Gnomad FIN AF: 0.000715

Gnomad MID AF: 0.0155

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0204

GnomAD4 exome AF: 0.0270 AC: 2 AN: 74 Hom.: 0 Cov.: 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 = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0238 AC: 2512 AN: 105534 Hom.: 49 Cov.: 23 AF XY: 0.0219 AC XY: 1076 AN XY: 49058

African (AFR) AF: 0.0540 AC: 1491 AN: 27632

American (AMR) AF: 0.0116 AC: 118 AN: 10200

Ashkenazi Jewish (ASJ) AF: 0.00969 AC: 27 AN: 2786

East Asian (EAS) AF: 0.00370 AC: 10 AN: 2706

South Asian (SAS) AF: 0.00606 AC: 18 AN: 2968

European-Finnish (FIN) AF: 0.000715 AC: 3 AN: 4194

Middle Eastern (MID) AF: 0.0169 AC: 3 AN: 178

European-Non Finnish (NFE) AF: 0.0152 AC: 802 AN: 52772

Other (OTH) AF: 0.0203 AC: 29 AN: 1428

Alfa AF: 0.00408 Hom.: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (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;