rs149614835

chr3-48645117-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001407.3(CELSR3):c.7890G>A(p.Met2630Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,606,028 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (51 hom.)
• Consequence: CELSR3 NM_001407.3 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 7.54

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CELSR3
• BP4: Computational evidence support a benign effect (MetaRNN=0.011453748).
• BP6: Variant 3-48645117-C-T is Benign according to our data. Variant chr3-48645117-C-T is described in ClinVar as [Benign]. Clinvar id is 40229.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48645117-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00177 (269/152350) while in subpopulation SAS AF= 0.019 (92/4834). AF 95% confidence interval is 0.0159. There are 2 homozygotes in gnomad4. There are 152 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 270 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CELSR3	NM_001407.3	c.7890G>A	p.Met2630Ile	missense_variant	25/35	ENST00000164024.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CELSR3	ENST00000164024.5	c.7890G>A	p.Met2630Ile	missense_variant	25/35	1	NM_001407.3	P1

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152232 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0190

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00393 AC: 976 AN: 248090 Hom.: 11 AF XY: 0.00500 AC XY: 674 AN XY: 134796

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0195

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.00398

GnomAD4 exome AF: 0.00245 AC: 3560 AN: 1453678 Hom.: 51 Cov.: 32 AF XY: 0.00304 AC XY: 2196 AN XY: 721530

Gnomad4 AFR exome AF: 0.000929

Gnomad4 AMR exome AF: 0.00169

Gnomad4 ASJ exome AF: 0.00937

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0181

Gnomad4 FIN exome AF: 0.000306

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152350 Hom.: 2 Cov.: 32 AF XY: 0.00204 AC XY: 152 AN XY: 74492

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00131

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00422 AC: 511

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00300

EpiControl AF: 0.00290

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Variant of unknown significance Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Feb 01, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.55		Loss of disorder (P = 0.0676);
MVP		0.81
MPC		0.98
ClinPred		0.038	T
GERP RS		5.2
Varity_R		0.50
gMVP		0.82

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: rs149614835; hg19: chr3-48682550;