rs905467

Variant names:

• chr1-5874440-T-C
• rs905467
• NM_015102.5:c.3231+31A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-5874440-T-C
• chr1-5874440-T-A
• chr1-5874440-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015102.5(NPHP4):​c.3231+31A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,486,024 control chromosomes in the GnomAD database, including 47,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3940 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43410 hom.)
• Consequence: NPHP4 NM_015102.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-5874440-T-C is Benign according to our data. Variant chr1-5874440-T-C is described in ClinVar as Benign. ClinVar VariationId is 260553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.415 is higher than 0.05.

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.3231+31A>G		intron	N/A	NP_055917.1	O75161-1
	NPHP4	NM_001291594.2		c.1695+31A>G		intron	N/A	NP_001278523.1
	NPHP4	NM_001291593.2		c.1692+31A>G		intron	N/A	NP_001278522.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP4	ENST00000378156.9	TSL:1 MANE Select	c.3231+31A>G		intron	N/A	ENSP00000367398.4	O75161-1
	NPHP4	ENST00000378169.7	TSL:1	n.*2132+31A>G		intron	N/A	ENSP00000367411.3	D6RA06
	NPHP4	ENST00000489180.6	TSL:2	n.*1042+31A>G		intron	N/A	ENSP00000423747.1	O75161-2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32693 AN: 151922 Hom.: 3941 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.237

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.272 AC: 30953 AN: 113764 AF XY: 0.280

Gnomad AFR exome AF: 0.0996

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.390

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.248 AC: 331310 AN: 1333984 Hom.: 43410 Cov.: 31 AF XY: 0.253 AC XY: 164742 AN XY: 650630

African (AFR) AF: 0.0990 AC: 2904 AN: 29324

American (AMR) AF: 0.304 AC: 7985 AN: 26260

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 4940 AN: 21430

East Asian (EAS) AF: 0.425 AC: 14879 AN: 35002

South Asian (SAS) AF: 0.417 AC: 29199 AN: 69992

European-Finnish (FIN) AF: 0.225 AC: 10492 AN: 46558

Middle Eastern (MID) AF: 0.276 AC: 1482 AN: 5370

European-Non Finnish (NFE) AF: 0.235 AC: 245187 AN: 1044978

Other (OTH) AF: 0.259 AC: 14242 AN: 55070

GnomAD4 genome AF: 0.215 AC: 32707 AN: 152040 Hom.: 3940 Cov.: 32 AF XY: 0.221 AC XY: 16439 AN XY: 74308

African (AFR) AF: 0.102 AC: 4228 AN: 41488

American (AMR) AF: 0.274 AC: 4188 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3468

East Asian (EAS) AF: 0.410 AC: 2110 AN: 5148

South Asian (SAS) AF: 0.430 AC: 2070 AN: 4810

European-Finnish (FIN) AF: 0.232 AC: 2449 AN: 10566

Middle Eastern (MID) AF: 0.281 AC: 82 AN: 292

European-Non Finnish (NFE) AF: 0.237 AC: 16107 AN: 67952

Other (OTH) AF: 0.216 AC: 456 AN: 2112

Alfa AF: 0.227 Hom.: 3511

Bravo AF: 0.209

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.47
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs905467; hg19: chr1-5934500; COSMIC: COSV65393891; COSMIC: COSV65393891;