rs749571139

Variant names:

• chr1-5927771-G-A
• rs749571139
• NM_015102.5:c.1319C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-5927771-G-A
• chr1-5927771-G-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001291594.2(NPHP4):​c.-48C>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 0.0000664 in 1,610,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: NPHP4 NM_001291594.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.49
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05225888).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000118 (18/151994) while in subpopulation AMR AF = 0.00111 (17/15258). AF 95% confidence interval is 0.000709. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291594.2. 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.1319C>T	p.Ser440Leu	missense	Exon 11 of 30	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 9 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.-48C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 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.1319C>T	p.Ser440Leu	missense	Exon 11 of 30	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*393C>T		non_coding_transcript_exon	Exon 10 of 27	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.1319C>T		non_coding_transcript_exon	Exon 11 of 33	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151994 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000185 AC: 46 AN: 249144 AF XY: 0.000133

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.0000610 AC: 89 AN: 1458800 Hom.: 0 Cov.: 31 AF XY: 0.0000552 AC XY: 40 AN XY: 725222

African (AFR) AF: 0.0000299 AC: 1 AN: 33438

American (AMR) AF: 0.000895 AC: 40 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1109440

Other (OTH) AF: 0.000116 AC: 7 AN: 60216

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151994 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00111 AC: 17 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000909 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000547

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Nephronophthisis (1)
-	1	-	Nephronophthisis 4 (1)
-	1	-	Senior-Loken syndrome 4 (1)
-	1	-	Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.013	B
Vest4		0.48
MutPred		0.22		Loss of sheet (P = 0.0315)
MVP		0.86
MPC		0.062
ClinPred		0.020	T
GERP RS		2.6
Varity_R		0.072
gMVP		0.30
Mutation Taster		=92/8	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: rs749571139; hg19: chr1-5987831; COSMIC: COSV65395853;