chr14-54962779-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_007086.4(WDHD1):​c.2606G>A​(p.Gly869Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

WDHD1
NM_007086.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.559
Variant links:
Genes affected
WDHD1 (HGNC:23170): (WD repeat and HMG-box DNA binding protein 1) The protein encoded by this gene contains multiple N-terminal WD40 domains and a C-terminal high mobility group (HMG) box. WD40 domains are found in a variety of eukaryotic proteins and may function as adaptor/regulatory modules in signal transduction, pre-mRNA processing and cytoskeleton assembly. HMG boxes are found in many eukaryotic proteins involved in chromatin assembly, transcription and replication. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03368455).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
WDHD1NM_007086.4 linkc.2606G>A p.Gly869Glu missense_variant Exon 20 of 26 ENST00000360586.8 NP_009017.1 O75717-1
WDHD1NM_001008396.3 linkc.2237G>A p.Gly746Glu missense_variant Exon 19 of 25 NP_001008397.1 O75717-2
WDHD1XM_006720012.2 linkc.2606G>A p.Gly869Glu missense_variant Exon 20 of 26 XP_006720075.1
WDHD1XM_011536373.3 linkc.1517G>A p.Gly506Glu missense_variant Exon 11 of 17 XP_011534675.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
WDHD1ENST00000360586.8 linkc.2606G>A p.Gly869Glu missense_variant Exon 20 of 26 1 NM_007086.4 ENSP00000353793.3 O75717-1
WDHD1ENST00000420358.2 linkc.2237G>A p.Gly746Glu missense_variant Exon 19 of 25 5 ENSP00000399349.2 O75717-2
WDHD1ENST00000567693.1 linkn.*1056G>A non_coding_transcript_exon_variant Exon 8 of 14 2 ENSP00000456806.1 H3BSQ1
WDHD1ENST00000567693.1 linkn.*1056G>A 3_prime_UTR_variant Exon 8 of 14 2 ENSP00000456806.1 H3BSQ1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251142
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000466
Gnomad NFE exome
AF:
0.0000792
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461552
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
727066
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000753
Gnomad4 NFE exome
AF:
0.0000288
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
ExAC
AF:
0.0000659
AC:
8

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 11, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2606G>A (p.G869E) alteration is located in exon 20 (coding exon 19) of the WDHD1 gene. This alteration results from a G to A substitution at nucleotide position 2606, causing the glycine (G) at amino acid position 869 to be replaced by a glutamic acid (E). 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
Benign
0.060
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
4.5
DANN
Benign
0.35
DEOGEN2
Benign
0.00063
T;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.98
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.62
T;T
M_CAP
Benign
0.0082
T
MetaRNN
Benign
0.034
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.58
N;.
PrimateAI
Benign
0.22
T
PROVEAN
Benign
1.4
N;N
REVEL
Benign
0.063
Sift
Benign
1.0
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0
B;.
Vest4
0.13
MVP
0.43
MPC
0.046
ClinPred
0.014
T
GERP RS
1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.021
gMVP
0.035

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

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

Other links and lift over

dbSNP: rs762950965; hg19: chr14-55429497; API