rs41276501

chr3-9944066-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000326434.9(CRELD1):c.1213C>G(p.Gln405Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 800,866 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (1 hom.)
• Consequence: CRELD1 ENST00000326434.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.934

Genes affected

CRELD1 (HGNC:14630): (cysteine rich with EGF like domains 1) This gene encodes a member of a subfamily of epidermal growth factor-related proteins. The encoded protein is characterized by a cysteine-rich with epidermal growth factor-like domain. This protein may function as a cell adhesion molecule. Mutations in this gene are the cause of atrioventricular septal defect. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Apr 2010]

(HGNC:):

PRRT3 (HGNC:26591): (proline rich transmembrane protein 3) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009648323).
• BP6: Variant 3-9944066-C-G is Benign according to our data. Variant chr3-9944066-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 465833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-9944066-C-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRELD1	NM_001077415.3	c.1049-299C>G		intron_variant		ENST00000452070.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRELD1	ENST00000452070.6	c.1049-299C>G		intron_variant		2	NM_001077415.3	P1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000586 AC: 146 AN: 249022 Hom.: 1 AF XY: 0.000682 AC XY: 92 AN XY: 134816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000776 AC: 503 AN: 648526 Hom.: 1 Cov.: 6 AF XY: 0.000809 AC XY: 285 AN XY: 352230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000663

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000428

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000725 AC XY: 54 AN XY: 74496

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000952 Hom.: 0

Bravo AF: 0.000812

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.00131

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CRELD1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Atrioventricular septal defect, susceptibility to, 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

CRELD1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 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
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	4.7
Dann	Benign	0.92
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.023
Sift	Benign	0.057	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.029	B
Vest4		0.12
MVP		0.24
MPC		0.19
ClinPred		0.019	T
GERP RS		-2.0
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs41276501; hg19: chr3-9985750; COSMIC: COSV99926221; COSMIC: COSV99926221;