chr12-48981230-C-T

Variant names:

• chr12-48981230-C-T
• rs387907359
• NM_005430.4:c.703C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005430.4(WNT1):​c.703C>T​(p.Arg235Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WNT1 NM_005430.4 missense
• Clinical Significance: risk factor no assertion criteria provided O:1
• Conservation: PhyloP100: 0.698
• Publications: 8 publications found

Genes affected

WNT1 (HGNC:12774): (Wnt family member 1) 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. It is very conserved in evolution, and the protein encoded by this gene is known to be 98% identical to the mouse Wnt1 protein at the amino acid level. The studies in mouse indicate that the Wnt1 protein functions in the induction of the mesencephalon and cerebellum. This gene was originally considered as a candidate gene for Joubert syndrome, an autosomal recessive disorder with cerebellar hypoplasia as a leading feature. However, further studies suggested that the gene mutations might not have a significant role in Joubert syndrome. This gene is clustered with another family member, WNT10B, in the chromosome 12q13 region. [provided by RefSeq, Jul 2008]

WNT1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 15

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• idiopathic juvenile osteoporosis

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305774 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005430.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT1	NM_005430.4	MANE Select	c.703C>T	p.Arg235Trp	missense	Exon 4 of 4	NP_005421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WNT1	ENST00000293549.4	TSL:1 MANE Select	c.703C>T	p.Arg235Trp	missense	Exon 4 of 4	ENSP00000293549.3
	ENSG00000305774	ENST00000812875.1		n.146+641G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457946 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725244

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39322

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110590

Other (OTH) AF: 0.00 AC: 0 AN: 60222

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	OSTEOPOROSIS, EARLY-ONSET, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.70
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.58		Loss of MoRF binding (P = 0.0878)
MVP		0.91
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.84
gMVP		0.82
Mutation Taster		=21/79	disease causing

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: rs387907359; hg19: chr12-49375013;