3-48639681-C-G

Position:

• chr3-48639681-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001407.3(CELSR3):​c.9904G>C​(p.Asp3302His) variant causes a missense change. The variant allele was found at a frequency of 0.00329 in 1,613,294 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (68 hom.)
• Consequence: CELSR3 NM_001407.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004685253).
• BP6: Variant 3-48639681-C-G is Benign according to our data. Variant chr3-48639681-C-G is described in ClinVar as [Benign]. Clinvar id is 783378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR3	NM_001407.3	c.9904G>C	p.Asp3302His	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.9904G>C	p.Asp3302His	missense_variant	34/35	1	NM_001407.3	ENSP00000164024.4
CELSR3	ENST00000461362.5	n.1992G>C		non_coding_transcript_exon_variant	7/8	5
CELSR3	ENST00000498057.1	n.3656G>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2598 AN: 152088 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0591

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00911

GnomAD3 exomes AF: 0.00452 AC: 1130 AN: 249728 Hom.: 27 AF XY: 0.00341 AC XY: 461 AN XY: 135332

Gnomad AFR exome AF: 0.0602

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000285

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00184 AC: 2692 AN: 1461088 Hom.: 68 Cov.: 33 AF XY: 0.00169 AC XY: 1229 AN XY: 726820

Gnomad4 AFR exome AF: 0.0617

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00469

GnomAD4 genome AF: 0.0172 AC: 2612 AN: 152206 Hom.: 72 Cov.: 32 AF XY: 0.0168 AC XY: 1252 AN XY: 74434

Gnomad4 AFR AF: 0.0593

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000832

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00901

Alfa AF: 0.00509 Hom.: 6

Bravo AF: 0.0202

ESP6500AA AF: 0.0588 AC: 259

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00574 AC: 696

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.63
MPC		1.0
ClinPred		0.030	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61729240; hg19: chr3-48677114;