1-5863367-A-T

Variant names:

• chr1-5863367-A-T
• rs35641267
• NM_015102.5:c.4179T>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_015102.5(NPHP4):​c.4179T>A​(p.Phe1393Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,613,996 control chromosomes in the GnomAD database, including 9 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 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: -0.455
• Publications: 8 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: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Senior-Loken syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28556257).
• BP6: Variant 1-5863367-A-T is Benign according to our data. Variant chr1-5863367-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95686.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00157 (239/152312) while in subpopulation NFE AF = 0.00284 (193/68020). AF 95% confidence interval is 0.00251. There are 0 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015102.5. 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
	NPHP4	NM_015102.5	MANE Select	c.4179T>A	p.Phe1393Leu	missense	Exon 30 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.2643T>A	p.Phe881Leu	missense	Exon 26 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2640T>A	p.Phe880Leu	missense	Exon 27 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.4179T>A	p.Phe1393Leu	missense	Exon 30 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*3080T>A		non_coding_transcript_exon	Exon 27 of 27	ENSP00000367411.3
	NPHP4	ENST00000460696.1	TSL:1	n.3411T>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00143 AC: 354 AN: 246924 AF XY: 0.00154

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000418

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00262 AC: 3828 AN: 1461684 Hom.: 9 Cov.: 32 AF XY: 0.00261 AC XY: 1898 AN XY: 727122

African (AFR) AF: 0.000388 AC: 13 AN: 33480

American (AMR) AF: 0.000537 AC: 24 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 67 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86256

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53398

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00317 AC: 3524 AN: 1111850

Other (OTH) AF: 0.00204 AC: 123 AN: 60372

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.00117 AC XY: 87 AN XY: 74484

African (AFR) AF: 0.000649 AC: 27 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68020

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00234 Hom.: 1

Bravo AF: 0.00151

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000477 AC: 2

ESP6500EA AF: 0.00250 AC: 21

ExAC AF: 0.00129 AC: 156

EpiCase AF: 0.00267

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	-	1	Nephronophthisis (1)
-	1	-	Nephronophthisis 4 (1)
-	-	1	not specified (1)
-	-	1	NPHP4-related disorder (1)
-	1	-	Retinal dystrophy (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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	0.65
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		-0.46
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.58		Loss of catalytic residue at F1393 (P = 0.0994)
MVP		0.90
MPC		0.42
ClinPred		0.16	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.78
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35641267; hg19: chr1-5923427;