4-39182543-G-T

Position:

• chr4-39182543-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025132.4(WDR19):​c.-15G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00443 in 1,613,766 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (17 hom.)
• Consequence: WDR19 NM_025132.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.18

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-39182543-G-T is Benign according to our data. Variant chr4-39182543-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 348722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-39182543-G-T is described in Lovd as [Benign]. Variant chr4-39182543-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00293 (446/152278) while in subpopulation NFE AF= 0.00513 (349/68022). AF 95% confidence interval is 0.00469. There are 3 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR19	NM_025132.4	c.-15G>T		5_prime_UTR_premature_start_codon_gain_variant	1/37	ENST00000399820.8	NP_079408.3
WDR19	NM_025132.4	c.-15G>T		5_prime_UTR_variant	1/37	ENST00000399820.8	NP_079408.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR19	ENST00000399820	c.-15G>T		5_prime_UTR_premature_start_codon_gain_variant	1/37	1	NM_025132.4	ENSP00000382717.3
WDR19	ENST00000399820	c.-15G>T		5_prime_UTR_variant	1/37	1	NM_025132.4	ENSP00000382717.3

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 444 AN: 152160 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00512

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00320 AC: 793 AN: 247890 Hom.: 3 AF XY: 0.00348 AC XY: 468 AN XY: 134632

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.000842

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00464

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00459 AC: 6710 AN: 1461488 Hom.: 17 Cov.: 31 AF XY: 0.00455 AC XY: 3305 AN XY: 727002

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00421

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00519

Gnomad4 OTH exome AF: 0.00467

GnomAD4 genome AF: 0.00293 AC: 446 AN: 152278 Hom.: 3 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74444

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00513

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00323

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Asphyxiating thoracic dystrophy 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cranioectodermal dysplasia 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.78
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs150860929; hg19: chr4-39184163;