18-56696286-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_015285.3(WDR7):ā€‹c.1402A>Gā€‹(p.Thr468Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000020 ( 0 hom., cov: 32)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

WDR7
NM_015285.3 missense

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.12
Variant links:
Genes affected
WDR7 (HGNC:13490): (WD repeat domain 7) 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) that 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. The encoded protein forms the beta subunit of rabconnectin-3 and binds directly with Rab3A GDP/GTP exchange protein and indirectly with Rab3A GDP/GTP activating protein; these proteins are regulators of Rab3 small G protein family members involved in control of the calcium-dependant exocytosis of neurotransmitters. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.845
BS2
High AC in GnomAdExome4 at 36 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WDR7NM_015285.3 linkuse as main transcriptc.1402A>G p.Thr468Ala missense_variant 12/28 ENST00000254442.8 NP_056100.2 Q9Y4E6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WDR7ENST00000254442.8 linkuse as main transcriptc.1402A>G p.Thr468Ala missense_variant 12/281 NM_015285.3 ENSP00000254442.3 Q9Y4E6-1
WDR7ENST00000357574.7 linkuse as main transcriptc.1402A>G p.Thr468Ala missense_variant 12/275 ENSP00000350187.2 Q9Y4E6-2
WDR7ENST00000589935.1 linkuse as main transcriptc.-1+44710A>G intron_variant 4 ENSP00000467485.1 K7EPQ4
WDR7ENST00000585754.1 linkuse as main transcriptn.408A>G non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251378
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000246
AC:
36
AN:
1461806
Hom.:
0
Cov.:
30
AF XY:
0.0000234
AC XY:
17
AN XY:
727196
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000306
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2023The c.1402A>G (p.T468A) alteration is located in exon 12 (coding exon 11) of the WDR7 gene. This alteration results from a A to G substitution at nucleotide position 1402, causing the threonine (T) at amino acid position 468 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
.;T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Benign
0.025
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Benign
1.8
L;L
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.019
D;D
Polyphen
0.99
D;P
Vest4
0.88
MutPred
0.67
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP
0.49
MPC
0.67
ClinPred
0.95
D
GERP RS
5.7
Varity_R
0.50
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs750295159; hg19: chr18-54363517; API