NM_015285.3:c.1618C>T

Variant names:

• chr18-56718003-C-T
• rs1598986524
• NM_015285.3:c.1618C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015285.3(WDR7):​c.1618C>T​(p.His540Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,700 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 (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR7 NM_015285.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR7	NM_015285.3	c.1618C>T	p.His540Tyr	missense_variant	Exon 13 of 28	ENST00000254442.8	NP_056100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR7	ENST00000254442.8	c.1618C>T	p.His540Tyr	missense_variant	Exon 13 of 28	1	NM_015285.3	ENSP00000254442.3
WDR7	ENST00000357574.7	c.1618C>T	p.His540Tyr	missense_variant	Exon 13 of 27	5		ENSP00000350187.2
WDR7	ENST00000589935.1	c.-1+66427C>T		intron_variant	Intron 1 of 1	4		ENSP00000467485.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461700 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1618C>T (p.H540Y) alteration is located in exon 13 (coding exon 12) of the WDR7 gene. This alteration results from a C to T substitution at nucleotide position 1618, causing the histidine (H) at amino acid position 540 to be replaced by a tyrosine (Y). 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	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.047	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.091	T;T
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.47		Loss of disorder (P = 0.1065);Loss of disorder (P = 0.1065);
MVP		0.42
MPC		1.2
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.82
gMVP		0.72

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: rs1598986524; hg19: chr18-54385234;