19-12669390-T-C

Position:

• chr19-12669390-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016145.4(WDR83OS):​c.14A>G​(p.Asn5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,599,780 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (21 hom., cov: 32)
  • Exomes 𝑓: 0.022 (389 hom.)
• Consequence: WDR83OS NM_016145.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.615

Genes affected

WDR83OS (HGNC:30203): (WD repeat domain 83 opposite strand) Enables protein folding chaperone. Involved in protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015950203).
• BP6: Variant 19-12669390-T-C is Benign according to our data. Variant chr19-12669390-T-C is described in ClinVar as [Benign]. Clinvar id is 2039517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0164 (2500/152266) while in subpopulation NFE AF= 0.0243 (1656/68022). AF 95% confidence interval is 0.0234. There are 21 homozygotes in gnomad4. There are 1213 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR83OS	NM_016145.4	c.14A>G	p.Asn5Ser	missense_variant	1/4	ENST00000596731.7
WDR83	NM_001099737.3	c.-36-365T>C		intron_variant		ENST00000418543.8
WDR83	NR_029375.2	n.307-365T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR83OS	ENST00000596731.7	c.14A>G	p.Asn5Ser	missense_variant	1/4	1	NM_016145.4	P4
WDR83	ENST00000418543.8	c.-36-365T>C		intron_variant		1	NM_001099737.3	P1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2501 AN: 152148 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0243

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0159 AC: 3597 AN: 226092 Hom.: 35 AF XY: 0.0162 AC XY: 1972 AN XY: 122040

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.00849

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.000176

Gnomad SAS exome AF: 0.0148

Gnomad FIN exome AF: 0.0195

Gnomad NFE exome AF: 0.0227

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0221 AC: 31946 AN: 1447514 Hom.: 389 Cov.: 32 AF XY: 0.0216 AC XY: 15538 AN XY: 718768

Gnomad4 AFR exome AF: 0.00322

Gnomad4 AMR exome AF: 0.00949

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0195

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0164 AC: 2500 AN: 152266 Hom.: 21 Cov.: 32 AF XY: 0.0163 AC XY: 1213 AN XY: 74458

Gnomad4 AFR AF: 0.00452

Gnomad4 AMR AF: 0.0170

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0243

Gnomad4 OTH AF: 0.0165

Alfa AF: 0.0210 Hom.: 51

Bravo AF: 0.0164

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0242 AC: 208

ExAC AF: 0.0149 AC: 1807

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.16
DANN	Benign	0.68
DEOGEN2	Benign	0.011	.;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	.;N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.25	.;.;N
REVEL	Benign	0.047
Sift	Benign	0.54	.;.;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.066, 0.073
MPC		0.25
ClinPred		0.0028	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.051
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs117131055; hg19: chr19-12780204;