rs377060857

Variant names:

• chr3-132722251-C-T
• rs377060857
• NM_153240.5:c.105G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_153240.5(NPHP3):​c.105G>A​(p.Lys35Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,573,042 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: NPHP3 NM_153240.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.941
• 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-AS1 (HGNC:24129): (NPHP3 antisense RNA 1)

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-132722251-C-T is Benign according to our data. Variant chr3-132722251-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193504.
• BP7: Synonymous conserved (PhyloP=0.941 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00103 (156/152098) while in subpopulation SAS AF = 0.00601 (29/4826). AF 95% confidence interval is 0.0043. There are 0 homozygotes in GnomAd4. There are 84 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	NM_153240.5	MANE Select	c.105G>A	p.Lys35Lys	synonymous	Exon 1 of 27	NP_694972.3
	NPHP3-AS1	NR_002811.2		n.502C>T		non_coding_transcript_exon	Exon 1 of 11
	NPHP3-ACAD11	NR_037804.1		n.209G>A		non_coding_transcript_exon	Exon 1 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.105G>A	p.Lys35Lys	synonymous	Exon 1 of 27	ENSP00000338766.5
	NPHP3	ENST00000383282.3	TSL:1	c.105G>A	p.Lys35Lys	synonymous	Exon 1 of 2	ENSP00000372769.2
	NPHP3-AS1	ENST00000489343.5	TSL:1	n.502C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00102

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00159 AC: 318 AN: 200076 AF XY: 0.00199

Gnomad AFR exome AF: 0.000222

Gnomad AMR exome AF: 0.000803

Gnomad ASJ exome AF: 0.00478

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000424

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00109 AC: 1553 AN: 1420944 Hom.: 13 Cov.: 31 AF XY: 0.00128 AC XY: 902 AN XY: 707138

African (AFR) AF: 0.0000664 AC: 2 AN: 30142

American (AMR) AF: 0.000830 AC: 35 AN: 42144

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 112 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 36438

South Asian (SAS) AF: 0.00545 AC: 455 AN: 83538

European-Finnish (FIN) AF: 0.000498 AC: 19 AN: 38178

Middle Eastern (MID) AF: 0.00890 AC: 46 AN: 5168

European-Non Finnish (NFE) AF: 0.000726 AC: 799 AN: 1101032

Other (OTH) AF: 0.00144 AC: 85 AN: 59050

GnomAD4 genome AF: 0.00103 AC: 156 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74362

African (AFR) AF: 0.000144 AC: 6 AN: 41530

American (AMR) AF: 0.00190 AC: 29 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10572

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00102 AC: 69 AN: 67958

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.000948

Asia WGS AF: 0.00145 AC: 5 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (1)
-	1	-	NPHP3-related Meckel-like syndrome (1)
-	-	1	Renal-hepatic-pancreatic dysplasia 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.90
PhyloP100		0.94
PromoterAI		0.043	Neutral
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: rs377060857; hg19: chr3-132441095;