chr1-22129653-G-A

Position:

• chr1-22129653-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_030761.5(WNT4):​c.276C>T​(p.Leu92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,726 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (22 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (15 hom.)
• Consequence: WNT4 NM_030761.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.914

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-22129653-G-A is Benign according to our data. Variant chr1-22129653-G-A is described in ClinVar as [Benign]. Clinvar id is 772252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.914 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0094 (1431/152282) while in subpopulation AFR AF= 0.0324 (1348/41556). AF 95% confidence interval is 0.031. There are 22 homozygotes in gnomad4. There are 685 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WNT4	NM_030761.5	c.276C>T	p.Leu92=	synonymous_variant	2/5	ENST00000290167.11	NP_110388.2
WNT4	XM_011541597.3	c.342C>T	p.Leu114=	synonymous_variant	2/5		XP_011539899.1
WNT4	XM_011541599.2	c.342C>T	p.Leu114=	synonymous_variant	2/3		XP_011539901.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WNT4	ENST00000290167.11	c.276C>T	p.Leu92=	synonymous_variant	2/5	1	NM_030761.5	ENSP00000290167	P1
WNT4	ENST00000415567.1	c.201C>T	p.Leu67=	synonymous_variant	1/2	2		ENSP00000403334
WNT4	ENST00000441048.1	c.111C>T	p.Leu37=	synonymous_variant	2/3	5		ENSP00000388925

Frequencies

GnomAD3 genomes AF: 0.00938 AC: 1428 AN: 152164 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00242 AC: 605 AN: 250172 Hom.: 6 AF XY: 0.00177 AC XY: 240 AN XY: 135416

Gnomad AFR exome AF: 0.0334

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000948 AC: 1386 AN: 1461444 Hom.: 15 Cov.: 32 AF XY: 0.000785 AC XY: 571 AN XY: 727020

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00940 AC: 1431 AN: 152282 Hom.: 22 Cov.: 33 AF XY: 0.00920 AC XY: 685 AN XY: 74460

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.00385

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00333 Hom.: 3

Bravo AF: 0.0102

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	8.1
DANN	Benign	0.70

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: rs16826648; hg19: chr1-22456146;