rs16995209

Variant names:

• chr4-39266129-G-A
• rs16995209
• NM_025132.4:c.3250G>A

Variant summary

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

The NM_025132.4(WDR19):​c.3250G>A​(p.Gly1084Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,562,844 control chromosomes in the GnomAD database, including 496 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. G1084V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (262 hom., cov: 31)
  • Exomes 𝑓: 0.0033 (234 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 9.27
• Publications: 7 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=0.0032558143).
• BP6: Variant 4-39266129-G-A is Benign according to our data. Variant chr4-39266129-G-A is described in ClinVar as Benign. ClinVar VariationId is 261863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

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.3250G>A	p.Gly1084Ser	missense	Exon 29 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.2770G>A	p.Gly924Ser	missense	Exon 28 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.3250G>A	p.Gly1084Ser	missense	Exon 29 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.3262G>A	p.Gly1088Ser	missense	Exon 29 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.3184G>A	p.Gly1062Ser	missense	Exon 28 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5005 AN: 152114 Hom.: 261 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.00778 AC: 1366 AN: 175504 AF XY: 0.00596

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00334 AC: 4716 AN: 1410612 Hom.: 234 Cov.: 30 AF XY: 0.00295 AC XY: 2056 AN XY: 696588

African (AFR) AF: 0.115 AC: 3681 AN: 32048

American (AMR) AF: 0.00674 AC: 251 AN: 37228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25326

East Asian (EAS) AF: 0.00 AC: 0 AN: 36718

South Asian (SAS) AF: 0.000163 AC: 13 AN: 79560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50290

Middle Eastern (MID) AF: 0.00438 AC: 25 AN: 5710

European-Non Finnish (NFE) AF: 0.000310 AC: 336 AN: 1085158

Other (OTH) AF: 0.00700 AC: 410 AN: 58574

GnomAD4 genome AF: 0.0329 AC: 5010 AN: 152232 Hom.: 262 Cov.: 31 AF XY: 0.0316 AC XY: 2356 AN XY: 74444

African (AFR) AF: 0.114 AC: 4721 AN: 41510

American (AMR) AF: 0.0123 AC: 188 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68014

Other (OTH) AF: 0.0242 AC: 51 AN: 2110

Alfa AF: 0.0113 Hom.: 383

Bravo AF: 0.0376

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.104 AC: 417

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.00723 AC: 843

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Asphyxiating thoracic dystrophy 5 (2)
-	-	2	Cranioectodermal dysplasia 4 (2)
-	-	1	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Nephronophthisis 13 (1)
-	-	1	Senior-Loken syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.77	P
Vest4		0.78
MVP		0.77
MPC		0.45
ClinPred		0.080	T
GERP RS		5.4
Varity_R		0.62
gMVP		0.70
Mutation Taster		=59/41	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: rs16995209; hg19: chr4-39267749;