chr4-39253208-A-C

Variant names:

• chr4-39253208-A-C
• rs187546086
• NM_025132.4:c.2792A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_025132.4(WDR19):​c.2792A>C​(p.Tyr931Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0056 in 1,613,688 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (31 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:10
• Conservation: PhyloP100: 3.81
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022140175).
• BP6: Variant 4-39253208-A-C is Benign according to our data. Variant chr4-39253208-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167843.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00259 (394/152330) while in subpopulation NFE AF = 0.00492 (335/68036). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 31 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.2792A>C	p.Tyr931Ser	missense	Exon 25 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.2312A>C	p.Tyr771Ser	missense	Exon 24 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.2792A>C	p.Tyr931Ser	missense	Exon 25 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.2804A>C	p.Tyr935Ser	missense	Exon 25 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.2726A>C	p.Tyr909Ser	missense	Exon 24 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152212 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00279 AC: 695 AN: 248780 AF XY: 0.00282

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00550

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00592 AC: 8650 AN: 1461358 Hom.: 31 Cov.: 31 AF XY: 0.00572 AC XY: 4156 AN XY: 726944

African (AFR) AF: 0.000777 AC: 26 AN: 33468

American (AMR) AF: 0.000627 AC: 28 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86200

European-Finnish (FIN) AF: 0.000937 AC: 50 AN: 53386

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.00754 AC: 8382 AN: 1111726

Other (OTH) AF: 0.00255 AC: 154 AN: 60358

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152330 Hom.: 0 Cov.: 31 AF XY: 0.00219 AC XY: 163 AN XY: 74486

African (AFR) AF: 0.000890 AC: 37 AN: 41580

American (AMR) AF: 0.000850 AC: 13 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00492 AC: 335 AN: 68036

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00442 Hom.: 15

Bravo AF: 0.00278

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00109 AC: 4

ESP6500EA AF: 0.00561 AC: 46

ExAC AF: 0.00265 AC: 320

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00475

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	-	2	not specified (2)
-	-	1	Asphyxiating thoracic dystrophy 5 (1)
-	-	1	Asphyxiating thoracic dystrophy 5;C4225376:Senior-Loken syndrome 8 (1)
-	1	-	Connective tissue disorder (1)
-	-	1	Cranioectodermal dysplasia 4 (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	WDR19-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.010	B
Vest4		0.71
MVP		0.76
MPC		0.24
ClinPred		0.027	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.59
Mutation Taster		=97/3	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: rs187546086; hg19: chr4-39254828; COSMIC: COSV56470385;