3-132688637-TA-TAA

Variant names:

• chr3-132688637-T-TA
• rs11396595
• NM_153240.5:c.3125+12dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_153240.5(NPHP3):​c.3125+12dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,178 control chromosomes in the GnomAD database, including 21,887 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2054 hom., cov: 30)
  • Exomes 𝑓: 0.14 (19833 hom.)
• Consequence: NPHP3 NM_153240.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.44
• 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 -16 ACMG points.

• BP6: Variant 3-132688637-T-TA is Benign according to our data. Variant chr3-132688637-T-TA is described in ClinVar as Benign. ClinVar VariationId is 262702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.563 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.3125+12dupT		intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3131+12dupT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3125+12_3125+13insT		intron	N/A	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000971413.1		c.2924+12_2924+13insT		intron	N/A	ENSP00000641472.1
	NPHP3	ENST00000971412.1		c.2702+12_2702+13insT		intron	N/A	ENSP00000641471.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20987 AN: 152118 Hom.: 2063 Cov.: 30

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0847

Gnomad EAS AF: 0.582

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.140

GnomAD2 exomes AF: 0.161 AC: 39864 AN: 248228 AF XY: 0.161

Gnomad AFR exome AF: 0.0894

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.0860

Gnomad EAS exome AF: 0.586

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.129

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.144 AC: 210210 AN: 1460942 Hom.: 19833 Cov.: 33 AF XY: 0.145 AC XY: 105382 AN XY: 726812

African (AFR) AF: 0.0847 AC: 2835 AN: 33460

American (AMR) AF: 0.0790 AC: 3532 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0863 AC: 2254 AN: 26124

East Asian (EAS) AF: 0.592 AC: 23487 AN: 39680

South Asian (SAS) AF: 0.168 AC: 14498 AN: 86242

European-Finnish (FIN) AF: 0.169 AC: 9031 AN: 53332

Middle Eastern (MID) AF: 0.104 AC: 598 AN: 5766

European-Non Finnish (NFE) AF: 0.130 AC: 144973 AN: 1111264

Other (OTH) AF: 0.149 AC: 9002 AN: 60352

GnomAD4 genome AF: 0.138 AC: 20975 AN: 152236 Hom.: 2054 Cov.: 30 AF XY: 0.143 AC XY: 10627 AN XY: 74428

African (AFR) AF: 0.0906 AC: 3764 AN: 41558

American (AMR) AF: 0.106 AC: 1626 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0847 AC: 294 AN: 3472

East Asian (EAS) AF: 0.581 AC: 3000 AN: 5166

South Asian (SAS) AF: 0.194 AC: 938 AN: 4830

European-Finnish (FIN) AF: 0.170 AC: 1804 AN: 10602

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9122 AN: 67996

Other (OTH) AF: 0.137 AC: 290 AN: 2112

Alfa AF: 0.125 Hom.: 241

Bravo AF: 0.130

Asia WGS AF: 0.317 AC: 1100 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis (2)
-	-	1	Meckel-Gruber syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs11396595; hg19: chr3-132407481; COSMIC: COSV107368243; COSMIC: COSV107368243;