1-27303669-C-T

Position:

• chr1-27303669-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_001276252.2(WDTC1):​c.1517C>T​(p.Thr506Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,611,602 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: WDTC1 NM_001276252.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

Genes affected

WDTC1 (HGNC:29175): (WD and tetratricopeptide repeats 1) Predicted to enable enzyme inhibitor activity; histone binding activity; and histone deacetylase binding activity. Predicted to be involved in negative regulation of fatty acid biosynthetic process. Predicted to act upstream of or within several processes, including cellular response to insulin stimulus; glucose metabolic process; and negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of Cul4-RING E3 ubiquitin ligase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, WDTC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.03226435).
• BS2: High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDTC1	NM_001276252.2	c.1517C>T	p.Thr506Met	missense_variant	14/16	ENST00000319394.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDTC1	ENST00000319394.8	c.1517C>T	p.Thr506Met	missense_variant	14/16	1	NM_001276252.2	P5
WDTC1	ENST00000361771.7	c.1514C>T	p.Thr505Met	missense_variant	14/16	1		A1
WDTC1	ENST00000491239.2	n.1191C>T		non_coding_transcript_exon_variant	9/10	2
WDTC1	ENST00000447062.2	c.1517C>T	p.Thr506Met	missense_variant, NMD_transcript_variant	13/16	2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000228 AC: 56 AN: 245722 Hom.: 0 AF XY: 0.000217 AC XY: 29 AN XY: 133606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000297

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000228 AC: 333 AN: 1459234 Hom.: 0 Cov.: 30 AF XY: 0.000240 AC XY: 174 AN XY: 725920

Gnomad4 AFR exome AF: 0.0000901

Gnomad4 AMR exome AF: 0.0000452

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000699

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74506

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2021

The c.1514C>T (p.T505M) alteration is located in exon 14 (coding exon 13) of the WDTC1 gene. This alteration results from a C to T substitution at nucleotide position 1514, causing the threonine (T) at amino acid position 505 to be replaced by a methionine (M). 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	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	0.63	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.054
Sift	Benign	0.14	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.66	P;P
Vest4		0.14
MVP		0.068
MPC		1.4
ClinPred		0.039	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.35

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: rs41291068; hg19: chr1-27630160;