NM_025132.4:c.1607G>C

Variant names:

• chr4-39225011-G-C
• rs115348383
• NM_025132.4:c.1607G>C

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.1607G>C​(p.Ser536Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00153 in 1,565,234 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (21 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.63
• Publications: 4 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=0.0073901117).
• BP6: Variant 4-39225011-G-C is Benign according to our data. Variant chr4-39225011-G-C is described in ClinVar as Benign. ClinVar VariationId is 261859.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 = 0.00837 (1273/152124) while in subpopulation AFR AF = 0.0287 (1191/41522). AF 95% confidence interval is 0.0273. There are 17 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.1607G>C	p.Ser536Thr	missense	Exon 15 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.1127G>C	p.Ser376Thr	missense	Exon 14 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.1607G>C	p.Ser536Thr	missense	Exon 15 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.1607G>C	p.Ser536Thr	missense	Exon 15 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.1541G>C	p.Ser514Thr	missense	Exon 14 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.00835 AC: 1269 AN: 152006 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00196 AC: 361 AN: 184362 AF XY: 0.00151

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000249

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000798 AC: 1127 AN: 1413110 Hom.: 21 Cov.: 32 AF XY: 0.000707 AC XY: 494 AN XY: 698532

African (AFR) AF: 0.0296 AC: 949 AN: 32052

American (AMR) AF: 0.00190 AC: 68 AN: 35842

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25254

East Asian (EAS) AF: 0.00 AC: 0 AN: 38454

South Asian (SAS) AF: 0.0000258 AC: 2 AN: 77530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51222

Middle Eastern (MID) AF: 0.000534 AC: 3 AN: 5616

European-Non Finnish (NFE) AF: 0.0000119 AC: 13 AN: 1088578

Other (OTH) AF: 0.00157 AC: 92 AN: 58562

GnomAD4 genome AF: 0.00837 AC: 1273 AN: 152124 Hom.: 17 Cov.: 32 AF XY: 0.00818 AC XY: 608 AN XY: 74354

African (AFR) AF: 0.0287 AC: 1191 AN: 41522

American (AMR) AF: 0.00439 AC: 67 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67996

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00146 Hom.: 1

Bravo AF: 0.0100

ESP6500AA AF: 0.0263 AC: 95

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.00170 AC: 204

Asia WGS AF: 0.000289 AC: 1 AN: 3476

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)
-	-	2	not specified (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	0.094
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.78
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.014
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.3	L
PhyloP100		5.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.42
Sift	Benign	0.45	T
Sift4G	Benign	0.95	T
Polyphen		0.010	B
Vest4		0.33
MVP		0.81
MPC		0.15
ClinPred		0.011	T
GERP RS		6.0
Varity_R		0.38
gMVP		0.55
Mutation Taster		=94/6	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: rs115348383; hg19: chr4-39226631;