3-132687229-TA-TAA

Variant names:

• chr3-132687229-T-TA
• rs398124547
• NM_153240.5:c.3126-4dupT

Variant summary

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

The NM_153240.5(NPHP3):​c.3126-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,216,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: NPHP3 NM_153240.5 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.265
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.3126-4dupT		splice_region intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3132-4dupT		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3126-4_3126-3insT		splice_region intron	N/A	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.2925-4_2925-3insT		splice_region intron	N/A	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.2703-4_2703-3insT		splice_region intron	N/A	ENSP00000641471.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151374 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 33 AN: 219134 AF XY: 0.000160

Gnomad AFR exome AF: 0.0000684

Gnomad AMR exome AF: 0.0000330

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000605

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.000131

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000327 AC: 348 AN: 1064784 Hom.: 0 Cov.: 16 AF XY: 0.000324 AC XY: 177 AN XY: 545894

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

African (AFR) AF: 0.0000388 AC: 1 AN: 25750

American (AMR) AF: 0.0000702 AC: 3 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.000172 AC: 4 AN: 23234

East Asian (EAS) AF: 0.0000535 AC: 2 AN: 37394

South Asian (SAS) AF: 0.000403 AC: 31 AN: 76882

European-Finnish (FIN) AF: 0.000358 AC: 17 AN: 47426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4964

European-Non Finnish (NFE) AF: 0.000361 AC: 274 AN: 759496

Other (OTH) AF: 0.000341 AC: 16 AN: 46910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151374 Hom.: 0 Cov.: 33 AF XY: 0.0000271 AC XY: 2 AN XY: 73902

African (AFR) AF: 0.00 AC: 0 AN: 41228

American (AMR) AF: 0.00 AC: 0 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67786

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NPHP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398124547;

hg19: chr3-132406073;