rs34391943

Variant names:

• chr3-132684574-C-T
• rs34391943
• NM_153240.5:c.3550G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-132684574-C-T
• chr3-132684574-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_153240.5(NPHP3):​c.3550G>A​(p.Ala1184Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00877 in 1,613,890 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1184V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0075 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0089 (87 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 6.14
• Publications: 15 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011167735).
• BP6: Variant 3-132684574-C-T is Benign according to our data. Variant chr3-132684574-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167378.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00749 (1140/152260) while in subpopulation NFE AF = 0.0113 (770/68002). AF 95% confidence interval is 0.0107. There are 12 homozygotes in GnomAd4. There are 571 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.3550G>A	p.Ala1184Thr	missense	Exon 24 of 27	NP_694972.3
	NPHP3-ACAD11	NR_037804.1		n.3556G>A		non_coding_transcript_exon	Exon 23 of 45

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP3	ENST00000337331.10	TSL:1 MANE Select	c.3550G>A	p.Ala1184Thr	missense	Exon 24 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3-ACAD11	ENST00000632629.1	TSL:2	c.196G>A	p.Ala66Thr	missense	Exon 1 of 5	ENSP00000488520.1	A0A0J9YXS1
	NPHP3	ENST00000971413.1		c.3349G>A	p.Ala1117Thr	missense	Exon 22 of 25	ENSP00000641472.1

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1140 AN: 152142 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0103

Gnomad FIN AF: 0.0105

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00823 AC: 2065 AN: 250872 AF XY: 0.00868

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.00890 AC: 13008 AN: 1461630 Hom.: 87 Cov.: 31 AF XY: 0.00924 AC XY: 6721 AN XY: 727122

African (AFR) AF: 0.00108 AC: 36 AN: 33474

American (AMR) AF: 0.00139 AC: 62 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0212 AC: 553 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.0103 AC: 892 AN: 86250

European-Finnish (FIN) AF: 0.0138 AC: 738 AN: 53392

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00911 AC: 10131 AN: 1111818

Other (OTH) AF: 0.00942 AC: 569 AN: 60388

GnomAD4 genome AF: 0.00749 AC: 1140 AN: 152260 Hom.: 12 Cov.: 32 AF XY: 0.00767 AC XY: 571 AN XY: 74460

African (AFR) AF: 0.00144 AC: 60 AN: 41554

American (AMR) AF: 0.00372 AC: 57 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4828

European-Finnish (FIN) AF: 0.0105 AC: 111 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 770 AN: 68002

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00999 Hom.: 33

Bravo AF: 0.00611

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00863 AC: 1048

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.00806

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	1	-	Bardet-Biedl syndrome (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
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		6.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.91
MPC		0.72
ClinPred		0.091	T
GERP RS		4.7
PromoterAI		-0.10	Neutral
Varity_R		0.74
gMVP		0.70
Mutation Taster		=88/12	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: rs34391943; hg19: chr3-132403418;