1-5927771-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015102.5(NPHP4):​c.1319C>G​(p.Ser440Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,800 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S440L) has been classified as Uncertain significance.

• 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: 2.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPHP4	NM_015102.5	c.1319C>G	p.Ser440Trp	missense_variant	Exon 11 of 30	ENST00000378156.9	NP_055917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPHP4	ENST00000378156.9	c.1319C>G	p.Ser440Trp	missense_variant	Exon 11 of 30	1	NM_015102.5	ENSP00000367398.4
NPHP4	ENST00000378169.7	n.*393C>G		non_coding_transcript_exon_variant	Exon 10 of 27	1		ENSP00000367411.3
NPHP4	ENST00000489180.6	n.1319C>G		non_coding_transcript_exon_variant	Exon 11 of 33	2		ENSP00000423747.1
NPHP4	ENST00000378169.7	n.*393C>G		3_prime_UTR_variant	Exon 10 of 27	1		ENSP00000367411.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458800 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0080	D;.
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.33		Loss of disorder (P = 8e-04);Loss of disorder (P = 8e-04);
MVP		0.93
MPC		0.43
ClinPred		0.91	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-5987831;