rs145643112

Variant names:

• chr3-132722202-C-T
• rs145643112
• NM_153240.5:c.154G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-132722202-C-T
• chr3-132722202-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.154G>A​(p.Ala52Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,509,996 control chromosomes in the GnomAD database, including 192 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A52V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (19 hom., cov: 32)
  • Exomes 𝑓: 0.013 (173 hom.)
• Consequence: NPHP3 NM_153240.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 1.85
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005204499).
• BP6: Variant 3-132722202-C-T is Benign according to our data. Variant chr3-132722202-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96509.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1580/152170) while in subpopulation NFE AF = 0.0164 (1115/67976). AF 95% confidence interval is 0.0156. There are 19 homozygotes in GnomAd4. There are 767 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.154G>A	p.Ala52Thr	missense	Exon 1 of 27	NP_694972.3
	NPHP3-AS1	NR_002811.2		n.453C>T		non_coding_transcript_exon	Exon 1 of 11
	NPHP3-ACAD11	NR_037804.1		n.258G>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.154G>A	p.Ala52Thr	missense	Exon 1 of 27	ENSP00000338766.5	Q7Z494-1
	NPHP3	ENST00000383282.3	TSL:1	c.154G>A	p.Ala52Thr	missense	Exon 1 of 2	ENSP00000372769.2	Q7Z494-7
	NPHP3-AS1	ENST00000489343.5	TSL:1	n.453C>T		non_coding_transcript_exon	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1580 AN: 152062 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0136 AC: 1656 AN: 121516 AF XY: 0.0144

Gnomad AFR exome AF: 0.00328

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.000137

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.0135 AC: 18296 AN: 1357826 Hom.: 173 Cov.: 31 AF XY: 0.0138 AC XY: 9278 AN XY: 671796

African (AFR) AF: 0.00156 AC: 44 AN: 28280

American (AMR) AF: 0.00200 AC: 63 AN: 31514

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 490 AN: 23306

East Asian (EAS) AF: 0.0000630 AC: 2 AN: 31760

South Asian (SAS) AF: 0.0135 AC: 1020 AN: 75584

European-Finnish (FIN) AF: 0.0178 AC: 637 AN: 35848

Middle Eastern (MID) AF: 0.00461 AC: 23 AN: 4992

European-Non Finnish (NFE) AF: 0.0143 AC: 15354 AN: 1070162

Other (OTH) AF: 0.0118 AC: 663 AN: 56380

GnomAD4 genome AF: 0.0104 AC: 1580 AN: 152170 Hom.: 19 Cov.: 32 AF XY: 0.0103 AC XY: 767 AN XY: 74402

African (AFR) AF: 0.00224 AC: 93 AN: 41546

American (AMR) AF: 0.00523 AC: 80 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4832

European-Finnish (FIN) AF: 0.0127 AC: 134 AN: 10578

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0164 AC: 1115 AN: 67976

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.0111 Hom.: 5

Bravo AF: 0.00876

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0166 AC: 64

ESP6500AA AF: 0.00184 AC: 5

ESP6500EA AF: 0.0151 AC: 88

ExAC AF: 0.0102 AC: 1107

Asia WGS AF: 0.00521 AC: 18 AN: 3466

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	1	1	Renal-hepatic-pancreatic dysplasia 1 (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Nephronophthisis 3 (1)
-	-	1	NPHP3-related Meckel-like syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	15
DANN	Uncertain	0.97
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.0	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.19	T
Polyphen		0.075	B
Vest4		0.46
MPC		0.18
ClinPred		0.0042	T
GERP RS		1.9
PromoterAI		-0.13	Neutral
Varity_R		0.043
gMVP		0.13
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: rs145643112; hg19: chr3-132441046; COSMIC: COSV58130357; COSMIC: COSV58130357;