1-22123994-C-T

Variant names:

• chr1-22123994-C-T
• rs2235529
• NM_030761.5:c.314-2418G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030761.5(WNT4):​c.314-2418G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 152,286 control chromosomes in the GnomAD database, including 2,302 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (2302 hom., cov: 32)
• Consequence: WNT4 NM_030761.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263
• Publications: 60 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• SERKAL syndrome

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030761.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT4	NM_030761.5	MANE Select	c.314-2418G>A		intron	N/A	NP_110388.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT4	ENST00000290167.11	TSL:1 MANE Select	c.314-2418G>A		intron	N/A	ENSP00000290167.5	P56705-1
	WNT4	ENST00000951124.1		c.314-2460G>A		intron	N/A	ENSP00000621183.1
	WNT4	ENST00000901549.1		c.314-2418G>A		intron	N/A	ENSP00000571608.1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21432 AN: 152168 Hom.: 2300 Cov.: 32

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.0766

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.135

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

GnomAD4 genome AF: 0.141 AC: 21441 AN: 152286 Hom.: 2302 Cov.: 32 AF XY: 0.148 AC XY: 11018 AN XY: 74462

African (AFR) AF: 0.0327 AC: 1359 AN: 41570

American (AMR) AF: 0.245 AC: 3743 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0766 AC: 266 AN: 3472

East Asian (EAS) AF: 0.500 AC: 2583 AN: 5166

South Asian (SAS) AF: 0.223 AC: 1073 AN: 4822

European-Finnish (FIN) AF: 0.157 AC: 1669 AN: 10616

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10188 AN: 68012

Other (OTH) AF: 0.134 AC: 284 AN: 2114

Alfa AF: 0.153 Hom.: 8338

Bravo AF: 0.146

Asia WGS AF: 0.306 AC: 1061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	7.4
DANN	Benign	0.75
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2235529; hg19: chr1-22450487;