3-132700297-A-G

Variant names:

• chr3-132700297-A-G
• rs145285316
• NM_153240.5:c.1743+37T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153240.5(NPHP3):​c.1743+37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,451,696 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (23 hom.)
• Consequence: NPHP3 NM_153240.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.319
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-132700297-A-G is Benign according to our data. Variant chr3-132700297-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 262692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (423/152330) while in subpopulation NFE AF = 0.00407 (277/68016). AF 95% confidence interval is 0.00368. There are 0 homozygotes in GnomAd4. There are 215 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.1743+37T>C		intron	N/A	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.1847+37T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.1743+37T>C		intron	N/A	ENSP00000338766.5
	NPHP3	ENST00000465756.5	TSL:5	n.1449+37T>C		intron	N/A	ENSP00000419907.1
	NPHP3	ENST00000469232.5	TSL:2	n.*1186+37T>C		intron	N/A	ENSP00000418664.1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00361 AC: 880 AN: 243652 AF XY: 0.00381

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00801

Gnomad NFE exome AF: 0.00450

Gnomad OTH exome AF: 0.00519

GnomAD4 exome AF: 0.00383 AC: 4983 AN: 1299366 Hom.: 23 Cov.: 19 AF XY: 0.00385 AC XY: 2522 AN XY: 654988

African (AFR) AF: 0.000497 AC: 15 AN: 30164

American (AMR) AF: 0.00188 AC: 83 AN: 44128

Ashkenazi Jewish (ASJ) AF: 0.000837 AC: 21 AN: 25078

East Asian (EAS) AF: 0.00 AC: 0 AN: 38800

South Asian (SAS) AF: 0.00386 AC: 318 AN: 82318

European-Finnish (FIN) AF: 0.00806 AC: 427 AN: 52950

Middle Eastern (MID) AF: 0.000365 AC: 2 AN: 5474

European-Non Finnish (NFE) AF: 0.00403 AC: 3887 AN: 965514

Other (OTH) AF: 0.00419 AC: 230 AN: 54940

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00289 AC XY: 215 AN XY: 74500

African (AFR) AF: 0.000505 AC: 21 AN: 41572

American (AMR) AF: 0.00183 AC: 28 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.00725 AC: 77 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00407 AC: 277 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00470 Hom.: 2

Bravo AF: 0.00192

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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: rs145285316; hg19: chr3-132419141;