chr3-48640019-C-T

Position:

• chr3-48640019-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001407.3(CELSR3):​c.9566G>A​(p.Arg3189Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: CELSR3 NM_001407.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.78

Genes affected

CELSR3 (HGNC:3230): (cadherin EGF LAG seven-pass G-type receptor 3) This gene belongs to the flamingo subfamily, which is included in the cadherin superfamily. The flamingo cadherins consist of nonclassic-type cadherins that do not interact with catenins. They are plasma membrane proteins containing seven epidermal growth factor-like repeats, nine cadherin domains and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic feature of their subfamily. The encoded protein may be involved in the regulation of contact-dependent neurite growth and may play a role in tumor formation. [provided by RefSeq, Jun 2013]

CELSR3 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008101523).
• BP6: Variant 3-48640019-C-T is Benign according to our data. Variant chr3-48640019-C-T is described in ClinVar as [Benign]. Clinvar id is 3042664.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 166 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR3	NM_001407.3	c.9566G>A	p.Arg3189Gln	missense_variant	34/35	ENST00000164024.5	NP_001398.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CELSR3	ENST00000164024.5	c.9566G>A	p.Arg3189Gln	missense_variant	34/35	1	NM_001407.3	ENSP00000164024.4
CELSR3	ENST00000461362.5	n.1654G>A		non_coding_transcript_exon_variant	7/8	5
CELSR3	ENST00000498057.1	n.3318G>A		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 166 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000865 AC: 213 AN: 246322 Hom.: 1 AF XY: 0.000863 AC XY: 116 AN XY: 134388

Gnomad AFR exome AF: 0.0000652

Gnomad AMR exome AF: 0.00235

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.00108 AC: 1580 AN: 1459566 Hom.: 1 Cov.: 34 AF XY: 0.00109 AC XY: 792 AN XY: 726120

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000389

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00109 AC: 166 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 80 AN XY: 74404

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00100 Hom.: 0

Bravo AF: 0.000899

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000729 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bladder exstrophy-epispadias-cloacal extrophy complex Benign:1

Benign, criteria provided, single submitter

research

Obstetrics and Gynecology Department, Johns Hopkins School Of Medicine

-

- -

CELSR3-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.052
Sift	Benign	0.092	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.27
MVP		0.43
MPC		0.31
ClinPred		0.018	T
GERP RS		3.3
Varity_R		0.077
gMVP		0.064

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

Publications

LitVar

Other links and lift over

dbSNP: rs144164666; hg19: chr3-48677452;