3-48639893-A-G

Position:

• chr3-48639893-A-G

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.9692T>C​(p.Val3231Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CELSR3 NM_001407.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.59

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0394893).
• BP6: Variant 3-48639893-A-G is Benign according to our data. Variant chr3-48639893-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2536003.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CELSR3	NM_001407.3	c.9692T>C	p.Val3231Ala	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.9692T>C	p.Val3231Ala	missense_variant	34/35	1	NM_001407.3	ENSP00000164024	P1
CELSR3	ENST00000461362.5	n.1780T>C		non_coding_transcript_exon_variant	7/8	5
CELSR3	ENST00000498057.1	n.3444T>C		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460932 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 726742

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.9
DANN	Benign	0.46
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.060
MutPred		0.068		Gain of relative solvent accessibility (P = 0.005);
MVP		0.17
MPC		0.32
ClinPred		0.022	T
GERP RS		2.2
Varity_R		0.015
gMVP		0.062

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-48677326; COSMIC: COSV105034357; COSMIC: COSV105034357;