rs138529452

Variant names:

• chr4-39231910-G-A
• rs138529452
• NM_025132.4:c.2096G>A

Variant summary

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

The NM_025132.4(WDR19):​c.2096G>A​(p.Arg699Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,613,494 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R699W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (22 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (20 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 9.47
• Publications: 6 publications found

Genes affected

WDR19 (HGNC:18340): (WD repeat domain 19) The protein encoded by this gene is a member of the WD (tryptophan-aspartic acid) repeat family, which is a large family of structurally-related proteins known to participate in a wide range of cellular processes. Each WD repeat typically contains about 40 amino acids that are usually bracketed by glycine-histidine and tryptophan-aspartic acid (WD) dipeptides. This protein contains six WD repeats, three transmembrane domains, and a clathrin heavy-chain repeat. Mutations in this gene have been described in individuals with a wide range of disorders affecting function of the cilium. These disorders are known as ciliopathies, and include Jeune syndrome, Sensenbrenner syndromes, Senior-Loken syndrome, combined or isolated nephronophthisis (NPHP), and retinitis pigmentosa (RP). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

WDR19 Gene-Disease associations (from GenCC):

• asphyxiating thoracic dystrophy 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• cranioectodermal dysplasia 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• nephronophthisis 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Senior-Loken syndrome 8

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• 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=0.0079551935).
• BP6: Variant 4-39231910-G-A is Benign according to our data. Variant chr4-39231910-G-A is described in ClinVar as Benign. ClinVar VariationId is 476155.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 = 0.0081 (1233/152182) while in subpopulation AFR AF = 0.0285 (1185/41508). AF 95% confidence interval is 0.0272. There are 22 homozygotes in GnomAd4. There are 584 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025132.4. 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
	WDR19	NM_025132.4	MANE Select	c.2096G>A	p.Arg699Gln	missense	Exon 18 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.1616G>A	p.Arg539Gln	missense	Exon 17 of 36	NP_001304853.1	B4DGR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR19	ENST00000399820.8	TSL:1 MANE Select	c.2096G>A	p.Arg699Gln	missense	Exon 18 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.2096G>A	p.Arg699Gln	missense	Exon 18 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.2030G>A	p.Arg677Gln	missense	Exon 17 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 1232 AN: 152064 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00196 AC: 488 AN: 249226 AF XY: 0.00151

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000819 AC: 1197 AN: 1461312 Hom.: 20 Cov.: 31 AF XY: 0.000729 AC XY: 530 AN XY: 726896

African (AFR) AF: 0.0293 AC: 982 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86240

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111532

Other (OTH) AF: 0.00166 AC: 100 AN: 60356

GnomAD4 genome AF: 0.00810 AC: 1233 AN: 152182 Hom.: 22 Cov.: 32 AF XY: 0.00785 AC XY: 584 AN XY: 74406

African (AFR) AF: 0.0285 AC: 1185 AN: 41508

American (AMR) AF: 0.00242 AC: 37 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00622 Hom.: 849

Bravo AF: 0.00862

ESP6500AA AF: 0.0233 AC: 89

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00250 AC: 302

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Asphyxiating thoracic dystrophy 5 (2)
-	-	2	Cranioectodermal dysplasia 4 (2)
-	-	2	not provided (2)
-	-	1	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	-	1	Nephronophthisis 13 (1)
-	-	1	Senior-Loken syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	-0.066	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.76
MVP		0.94
MPC		0.46
ClinPred		0.044	T
GERP RS		5.3
Varity_R		0.42
gMVP		0.64
Mutation Taster		=74/26	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: rs138529452; hg19: chr4-39233530; COSMIC: COSV107310544; COSMIC: COSV107310544;