rs12142270

Variant names:

• chr1-5986204-G-A
• rs12142270
• NM_015102.5:c.86C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291593.2(NPHP4):​c.-1144C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,662 control chromosomes in the GnomAD database, including 922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (187 hom., cov: 33)
  • Exomes 𝑓: 0.027 (735 hom.)
• Consequence: NPHP4 NM_001291593.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.911
• Publications: 11 publications found

Genes affected

NPHP4 (HGNC:19104): (nephrocystin 4) This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

NPHP4 Gene-Disease associations (from GenCC):

• nephronophthisis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• nephronophthisis 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019364357).
• BP6: Variant 1-5986204-G-A is Benign according to our data. Variant chr1-5986204-G-A is described in ClinVar as Benign. ClinVar VariationId is 260561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291593.2. 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
	NPHP4	NM_015102.5	MANE Select	c.86C>T	p.Thr29Met	missense	Exon 2 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291593.2		c.-1144C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 27	NP_001278522.1
	NPHP4	NM_001291593.2		c.-1144C>T		5_prime_UTR	Exon 2 of 27	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.86C>T	p.Thr29Met	missense	Exon 2 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.86C>T		non_coding_transcript_exon	Exon 2 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.86C>T		non_coding_transcript_exon	Exon 2 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.0419 AC: 6374 AN: 152154 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0866

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0432

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0248

Gnomad OTH AF: 0.0441

GnomAD2 exomes AF: 0.0291 AC: 7253 AN: 248848 AF XY: 0.0286

Gnomad AFR exome AF: 0.0877

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0449

Gnomad NFE exome AF: 0.0274

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0272 AC: 39757 AN: 1461390 Hom.: 735 Cov.: 31 AF XY: 0.0270 AC XY: 19635 AN XY: 726968

African (AFR) AF: 0.0913 AC: 3054 AN: 33468

American (AMR) AF: 0.0119 AC: 532 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 869 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.0332 AC: 2861 AN: 86212

European-Finnish (FIN) AF: 0.0445 AC: 2374 AN: 53366

Middle Eastern (MID) AF: 0.0352 AC: 203 AN: 5766

European-Non Finnish (NFE) AF: 0.0253 AC: 28099 AN: 1111674

Other (OTH) AF: 0.0292 AC: 1762 AN: 60368

GnomAD4 genome AF: 0.0419 AC: 6374 AN: 152272 Hom.: 187 Cov.: 33 AF XY: 0.0415 AC XY: 3089 AN XY: 74450

African (AFR) AF: 0.0863 AC: 3587 AN: 41542

American (AMR) AF: 0.0158 AC: 242 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0268 AC: 129 AN: 4822

European-Finnish (FIN) AF: 0.0432 AC: 458 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0248 AC: 1688 AN: 68016

Other (OTH) AF: 0.0436 AC: 92 AN: 2110

Alfa AF: 0.0292 Hom.: 371

Bravo AF: 0.0419

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0213 AC: 82

ESP6500AA AF: 0.0781 AC: 320

ESP6500EA AF: 0.0251 AC: 210

ExAC AF: 0.0320 AC: 3874

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0240

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Nephronophthisis 4 (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.91
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.25
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.21
MPC		0.081
ClinPred		0.011	T
GERP RS		3.8
Varity_R		0.050
gMVP		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs12142270; hg19: chr1-6046264; COSMIC: COSV65394927;