14-54962777-C-T

Variant names:

• chr14-54962777-C-T
• rs2041272917
• NM_007086.4:c.2608G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007086.4(WDHD1):​c.2608G>A​(p.Glu870Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 3.20

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17187873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDHD1	NM_007086.4	c.2608G>A	p.Glu870Lys	missense_variant	Exon 20 of 26	ENST00000360586.8	NP_009017.1
WDHD1	NM_001008396.3	c.2239G>A	p.Glu747Lys	missense_variant	Exon 19 of 25		NP_001008397.1
WDHD1	XM_006720012.2	c.2608G>A	p.Glu870Lys	missense_variant	Exon 20 of 26		XP_006720075.1
WDHD1	XM_011536373.3	c.1519G>A	p.Glu507Lys	missense_variant	Exon 11 of 17		XP_011534675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDHD1	ENST00000360586.8	c.2608G>A	p.Glu870Lys	missense_variant	Exon 20 of 26	1	NM_007086.4	ENSP00000353793.3
WDHD1	ENST00000420358.2	c.2239G>A	p.Glu747Lys	missense_variant	Exon 19 of 25	5		ENSP00000399349.2
WDHD1	ENST00000567693.1	n.*1058G>A		non_coding_transcript_exon_variant	Exon 8 of 14	2		ENSP00000456806.1
WDHD1	ENST00000567693.1	n.*1058G>A		3_prime_UTR_variant	Exon 8 of 14	2		ENSP00000456806.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2608G>A (p.E870K) 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 2608, causing the glutamic acid (E) at amino acid position 870 to be replaced by a lysine (K). 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	0.074
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0061	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.12
Sift	Benign	0.26	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.27	B;.
Vest4		0.33
MutPred		0.22		Gain of ubiquitination at E870 (P = 0.0031);.;
MVP		0.76
MPC		0.078
ClinPred		0.56	D
GERP RS		5.1
Varity_R		0.14
gMVP		0.15

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: rs2041272917; hg19: chr14-55429495;