1-22120823-A-G

Variant names:

• chr1-22120823-A-G
• rs3765350
• NM_030761.5:c.589-306T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_030761.5(WNT4):​c.589-306T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,026 control chromosomes in the GnomAD database, including 4,960 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4960 hom., cov: 32)
• Consequence: WNT4 NM_030761.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.368
• Publications: 30 publications found

Genes affected

WNT4 (HGNC:12783): (Wnt family member 4) The WNT gene family consists of structurally related genes which encode secreted signaling proteins. These proteins have been implicated in oncogenesis and in several developmental processes, including regulation of cell fate and patterning during embryogenesis. This gene is a member of the WNT gene family, and is the first signaling molecule shown to influence the sex-determination cascade. It encodes a protein which shows 98% amino acid identity to the Wnt4 protein of mouse and rat. This gene and a nuclear receptor known to antagonize the testis-determining factor play a concerted role in both the control of female development and the prevention of testes formation. This gene and another two family members, WNT2 and WNT7B, may be associated with abnormal proliferation in breast tissue. Mutations in this gene can result in Rokitansky-Kuster-Hauser syndrome and in SERKAL syndrome. [provided by RefSeq, Jul 2008]

WNT4 Gene-Disease associations (from GenCC):

• mullerian aplasia and hyperandrogenism

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
• SERKAL syndrome

  Inheritance: AR, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-22120823-A-G is Benign according to our data. Variant chr1-22120823-A-G is described in ClinVar as Benign. ClinVar VariationId is 1263499.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNT4	NM_030761.5	c.589-306T>C		intron_variant	Intron 4 of 4	ENST00000290167.11	NP_110388.2
WNT4	XM_011541597.3	c.655-306T>C		intron_variant	Intron 4 of 4		XP_011539899.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNT4	ENST00000290167.11	c.589-306T>C		intron_variant	Intron 4 of 4	1	NM_030761.5	ENSP00000290167.5

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35285 AN: 151908 Hom.: 4952 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.346

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.223

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.232 AC: 35312 AN: 152026 Hom.: 4960 Cov.: 32 AF XY: 0.241 AC XY: 17907 AN XY: 74316

African (AFR) AF: 0.173 AC: 7165 AN: 41488

American (AMR) AF: 0.339 AC: 5171 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 495 AN: 3468

East Asian (EAS) AF: 0.691 AC: 3561 AN: 5154

South Asian (SAS) AF: 0.347 AC: 1672 AN: 4812

European-Finnish (FIN) AF: 0.205 AC: 2173 AN: 10582

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14301 AN: 67932

Other (OTH) AF: 0.222 AC: 469 AN: 2112

Alfa AF: 0.233 Hom.: 9511

Bravo AF: 0.243

Asia WGS AF: 0.467 AC: 1619 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.67
DANN	Benign	0.26
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3765350; hg19: chr1-22447316;