14-54941632-C-G

Variant names:

• chr14-54941632-C-G
• NM_007086.4:c.3248G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007086.4(WDHD1):​c.3248G>C​(p.Arg1083Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDHD1 NM_007086.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDHD1	NM_007086.4	c.3248G>C	p.Arg1083Pro	missense_variant	Exon 26 of 26	ENST00000360586.8	NP_009017.1
WDHD1	NM_001008396.3	c.2879G>C	p.Arg960Pro	missense_variant	Exon 25 of 25		NP_001008397.1
WDHD1	XM_006720012.2	c.3242G>C	p.Arg1081Pro	missense_variant	Exon 26 of 26		XP_006720075.1
WDHD1	XM_011536373.3	c.2159G>C	p.Arg720Pro	missense_variant	Exon 17 of 17		XP_011534675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDHD1	ENST00000360586.8	c.3248G>C	p.Arg1083Pro	missense_variant	Exon 26 of 26	1	NM_007086.4	ENSP00000353793.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3248G>C (p.R1083P) alteration is located in exon 26 (coding exon 25) of the WDHD1 gene. This alteration results from a G to C substitution at nucleotide position 3248, causing the arginine (R) at amino acid position 1083 to be replaced by a proline (P). 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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.083	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Uncertain	-0.088	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;.
Vest4		0.52
MutPred		0.34		Loss of MoRF binding (P = 0.0094);.;
MVP		0.93
MPC		0.32
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.81
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-55408350;