rs150649460

Variant names:

• chr4-39228623-A-G
• rs150649460
• NM_025132.4:c.1915A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-39228623-A-G
• chr4-39228623-A-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.1915A>G​(p.Ser639Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000393 in 1,613,300 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: WDR19 NM_025132.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.197
• Publications: 0 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=0.005938649).
• BP6: Variant 4-39228623-A-G is Benign according to our data. Variant chr4-39228623-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261861.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 = 0.00202 (308/152314) while in subpopulation AFR AF = 0.00695 (289/41554). AF 95% confidence interval is 0.0063. There are 1 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1915A>G	p.Ser639Gly	missense	Exon 17 of 37	NP_079408.3
	WDR19	NM_001317924.2		c.1435A>G	p.Ser479Gly	missense	Exon 16 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.1915A>G	p.Ser639Gly	missense	Exon 17 of 37	ENSP00000382717.3	Q8NEZ3-1
	WDR19	ENST00000959578.1		c.1915A>G	p.Ser639Gly	missense	Exon 17 of 37	ENSP00000629637.1
	WDR19	ENST00000919861.1		c.1849A>G	p.Ser617Gly	missense	Exon 16 of 36	ENSP00000589920.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 305 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000543 AC: 135 AN: 248768 AF XY: 0.000370

Gnomad AFR exome AF: 0.00801

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000223 AC: 326 AN: 1460986 Hom.: 2 Cov.: 32 AF XY: 0.000194 AC XY: 141 AN XY: 726726

African (AFR) AF: 0.00834 AC: 279 AN: 33466

American (AMR) AF: 0.000224 AC: 10 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111418

Other (OTH) AF: 0.000481 AC: 29 AN: 60342

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74488

African (AFR) AF: 0.00695 AC: 289 AN: 41554

American (AMR) AF: 0.000915 AC: 14 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

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

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

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0201 Hom.: 2350

Bravo AF: 0.00245

ESP6500AA AF: 0.00738 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000679 AC: 82

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.010
DANN	Benign	0.52
DEOGEN2	Benign	0.079	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.20
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.16
Sift	Benign	0.48	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.059
MVP		0.34
MPC		0.15
ClinPred		0.0022	T
GERP RS		-4.6
Varity_R		0.033
gMVP		0.30
Mutation Taster		=100/0	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: rs150649460; hg19: chr4-39230243; COSMIC: COSV56466911;