chr1-5877257-T-G

Variant names:

• chr1-5877257-T-G
• rs112206586
• NM_015102.5:c.2653A>C

Variant summary

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

The NM_015102.5(NPHP4):​c.2653A>C​(p.Ser885Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,606,294 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. S885I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 35)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.385
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007251799).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000971 (148/152380) while in subpopulation AFR AF = 0.00332 (138/41604). AF 95% confidence interval is 0.00287. There are 1 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 35. 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_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.2653A>C	p.Ser885Arg	missense	Exon 20 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1117A>C	p.Ser373Arg	missense	Exon 16 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1114A>C	p.Ser372Arg	missense	Exon 17 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.2653A>C	p.Ser885Arg	missense	Exon 20 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*1554A>C		non_coding_transcript_exon	Exon 17 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*201A>C		non_coding_transcript_exon	Exon 21 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152262 Hom.: 1 Cov.: 35

Gnomad AFR AF: 0.00318

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000588

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000225 AC: 55 AN: 244084 AF XY: 0.000128

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000853 AC: 124 AN: 1453914 Hom.: 1 Cov.: 35 AF XY: 0.0000789 AC XY: 57 AN XY: 721992

African (AFR) AF: 0.00285 AC: 95 AN: 33380

American (AMR) AF: 0.000180 AC: 8 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39422

South Asian (SAS) AF: 0.0000817 AC: 7 AN: 85660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53132

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106188

Other (OTH) AF: 0.000234 AC: 14 AN: 59938

GnomAD4 genome AF: 0.000971 AC: 148 AN: 152380 Hom.: 1 Cov.: 35 AF XY: 0.000993 AC XY: 74 AN XY: 74518

African (AFR) AF: 0.00332 AC: 138 AN: 41604

American (AMR) AF: 0.000588 AC: 9 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000379 Hom.: 1

Bravo AF: 0.000963

ESP6500AA AF: 0.00164 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	NPHP4-related disorder (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	Nephronophthisis (1)
-	1	-	Senior-Loken syndrome 4;C1847013:Nephronophthisis 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.39
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	0.22	T
Sift4G	Benign	0.21	T
Polyphen		0.016	B
Vest4		0.14
MutPred		0.31		Gain of solvent accessibility (P = 0.0055)
MVP		0.87
MPC		0.081
ClinPred		0.0092	T
GERP RS		1.5
Varity_R		0.084
gMVP		0.35
Mutation Taster		=81/19	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: rs112206586; hg19: chr1-5937317;