rs144624477

Variant names:

• chr1-5865244-G-A
• rs144624477
• NM_015102.5:c.3674C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015102.5(NPHP4):​c.3674C>T​(p.Thr1225Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,584,646 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1225T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0054 (9 hom., cov: 34)
  • Exomes 𝑓: 0.00061 (10 hom.)
• Consequence: NPHP4 NM_015102.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.30
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015298545).
• BP6: Variant 1-5865244-G-A is Benign according to our data. Variant chr1-5865244-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00539 (821/152334) while in subpopulation AFR AF = 0.0182 (757/41584). AF 95% confidence interval is 0.0171. There are 9 homozygotes in GnomAd4. There are 396 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.3674C>T	p.Thr1225Met	missense	Exon 27 of 30	NP_055917.1
	NPHP4	NM_001291594.2		c.2138C>T	p.Thr713Met	missense	Exon 23 of 26	NP_001278523.1
	NPHP4	NM_001291593.2		c.2135C>T	p.Thr712Met	missense	Exon 24 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.3674C>T	p.Thr1225Met	missense	Exon 27 of 30	ENSP00000367398.4
	NPHP4	ENST00000378169.7	TSL:1	n.*2575C>T		non_coding_transcript_exon	Exon 24 of 27	ENSP00000367411.3
	NPHP4	ENST00000460696.1	TSL:1	n.1838C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 815 AN: 152218 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00135 AC: 306 AN: 226638 AF XY: 0.000867

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000859

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000989

Gnomad OTH exome AF: 0.000888

GnomAD4 exome AF: 0.000607 AC: 870 AN: 1432312 Hom.: 10 Cov.: 31 AF XY: 0.000485 AC XY: 343 AN XY: 707262

African (AFR) AF: 0.0203 AC: 668 AN: 32956

American (AMR) AF: 0.00109 AC: 47 AN: 43108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25626

East Asian (EAS) AF: 0.0000259 AC: 1 AN: 38656

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 84144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51524

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5474

European-Non Finnish (NFE) AF: 0.0000504 AC: 55 AN: 1091878

Other (OTH) AF: 0.00153 AC: 90 AN: 58946

GnomAD4 genome AF: 0.00539 AC: 821 AN: 152334 Hom.: 9 Cov.: 34 AF XY: 0.00532 AC XY: 396 AN XY: 74494

African (AFR) AF: 0.0182 AC: 757 AN: 41584

American (AMR) AF: 0.00255 AC: 39 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00617 AC: 13 AN: 2108

Alfa AF: 0.00121 Hom.: 2

Bravo AF: 0.00604

ESP6500AA AF: 0.0133 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00141 AC: 170

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Nephronophthisis 4 (2)
-	-	1	Kidney disorder (1)
-	-	1	Nephronophthisis (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Senior-Loken syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.18
Sift	Benign	0.036	D
Sift4G	Uncertain	0.013	D
Polyphen		0.53	P
Vest4		0.43
MVP		0.81
MPC		0.094
ClinPred		0.022	T
GERP RS		3.3
Varity_R		0.022
gMVP		0.36
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144624477; hg19: chr1-5925304; COSMIC: COSV107485032; COSMIC: COSV107485032;