chr1-5874534-G-T

Variant names:

• chr1-5874534-G-T
• rs376351293
• NM_015102.5:c.3168C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015102.5(NPHP4):​c.3168C>A​(p.His1056Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H1056H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.112611026).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	NM_015102.5	MANE Select	c.3168C>A	p.His1056Gln	missense	Exon 22 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.1632C>A	p.His544Gln	missense	Exon 18 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.1629C>A	p.His543Gln	missense	Exon 19 of 27	NP_001278522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3168C>A	p.His1056Gln	missense	Exon 22 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2069C>A		non_coding_transcript_exon	Exon 19 of 27	ENSP00000367411.3
	NPHP4	ENST00000489180.6	TSL:2	n.*979C>A		non_coding_transcript_exon	Exon 25 of 33	ENSP00000423747.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443332 Hom.: 0 Cov.: 34 AF XY: 0.00000140 AC XY: 1 AN XY: 715898

African (AFR) AF: 0.00 AC: 0 AN: 32984

American (AMR) AF: 0.00 AC: 0 AN: 42350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25610

East Asian (EAS) AF: 0.00 AC: 0 AN: 38836

South Asian (SAS) AF: 0.00 AC: 0 AN: 83056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1103510

Other (OTH) AF: 0.00 AC: 0 AN: 59620

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.027
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.064
Sift	Benign	0.069	T
Sift4G	Uncertain	0.035	D
Polyphen		0.38	B
Vest4		0.23
MutPred		0.23		Loss of catalytic residue at R1054 (P = 0.0421)
MVP		0.64
MPC		0.097
ClinPred		0.16	T
GERP RS		0.21
Varity_R		0.051
gMVP		0.39
Mutation Taster		=87/13	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: rs376351293; hg19: chr1-5934594;