2-19910722-G-A

Position:

• chr2-19910722-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001006657.2(WDR35):​c.*2836C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0228 in 152,246 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.023 (65 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: WDR35 NM_001006657.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.216

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-19910722-G-A is Benign according to our data. Variant chr2-19910722-G-A is described in ClinVar as [Benign]. Clinvar id is 333326.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-19910722-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2	c.*2836C>T		3_prime_UTR_variant	28/28	ENST00000345530.8
WDR35	NM_020779.4	c.*2836C>T		3_prime_UTR_variant	27/27	ENST00000281405.9
WDR35	XM_011533007.3	c.*2836C>T		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000281405.9	c.*2836C>T		3_prime_UTR_variant	27/27	1	NM_020779.4	P3
WDR35	ENST00000345530.8	c.*2836C>T		3_prime_UTR_variant	28/28	1	NM_001006657.2	A1

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3481 AN: 152128 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.00763

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0386

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.0859

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0440

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0187

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0228 AC: 3478 AN: 152246 Hom.: 65 Cov.: 33 AF XY: 0.0241 AC XY: 1797 AN XY: 74426

Gnomad4 AFR AF: 0.00763

Gnomad4 AMR AF: 0.0386

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.0859

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.0440

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0215 Hom.: 8

Bravo AF: 0.0214

Asia WGS AF: 0.0550 AC: 193 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cranioectodermal dysplasia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Short-rib thoracic dysplasia 7 with or without polydactyly Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.0
DANN	Benign	0.74

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: rs74469198; hg19: chr2-20110483;