14-54941681-T-G

Position:

• chr14-54941681-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007086.4(WDHD1):​c.3199A>C​(p.Asn1067His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 1,613,382 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (10 hom.)
• Consequence: WDHD1 NM_007086.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0920

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0080471635).
• BP6: Variant 14-54941681-T-G is Benign according to our data. Variant chr14-54941681-T-G is described in ClinVar as [Benign]. Clinvar id is 708577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00477 (727/152338) while in subpopulation AFR AF= 0.0167 (696/41576). AF 95% confidence interval is 0.0157. There are 5 homozygotes in gnomad4. There are 335 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDHD1	NM_007086.4	c.3199A>C	p.Asn1067His	missense_variant	26/26	ENST00000360586.8	NP_009017.1
WDHD1	NM_001008396.3	c.2830A>C	p.Asn944His	missense_variant	25/25		NP_001008397.1
WDHD1	XM_006720012.2	c.3193A>C	p.Asn1065His	missense_variant	26/26		XP_006720075.1
WDHD1	XM_011536373.3	c.2110A>C	p.Asn704His	missense_variant	17/17		XP_011534675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDHD1	ENST00000360586.8	c.3199A>C	p.Asn1067His	missense_variant	26/26	1	NM_007086.4	ENSP00000353793.3

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 724 AN: 152220 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00117 AC: 293 AN: 250288 Hom.: 1 AF XY: 0.000828 AC XY: 112 AN XY: 135256

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000496 AC: 725 AN: 1461044 Hom.: 10 Cov.: 31 AF XY: 0.000422 AC XY: 307 AN XY: 726742

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.000582

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.00477 AC: 727 AN: 152338 Hom.: 5 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74498

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000904 Hom.: 4

Bravo AF: 0.00531

ESP6500AA AF: 0.0150 AC: 66

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00140 AC: 170

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.85	D;D
MetaRNN	Benign	0.0080	T;T
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.27
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.71	P;.
Vest4		0.15
MVP		0.76
MPC		0.040
ClinPred		0.014	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
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: rs115022805; hg19: chr14-55408399; COSMIC: COSV99051870;