3-9934574-T-G

Variant names:

• chr3-9934574-T-G
• rs2125328927
• NM_001077415.3:c.136T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001077415.3(CRELD1):​c.136T>G​(p.Cys46Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRELD1 NM_001077415.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• Publications: 0 publications found

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]

CRELD1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• atrioventricular septal defect, susceptibility to, 2

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• Jeffries-Lakhani neurodevelopmental syndrome

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000288550 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRELD1	NM_001077415.3	c.136T>G	p.Cys46Gly	missense_variant	Exon 2 of 11	ENST00000452070.6	NP_001070883.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRELD1	ENST00000452070.6	c.136T>G	p.Cys46Gly	missense_variant	Exon 2 of 11	2	NM_001077415.3	ENSP00000393643.2
ENSG00000288550	ENST00000683484.1	n.1400-261T>G		intron_variant	Intron 16 of 23			ENSP00000507040.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 06, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.32	T;T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	.;.;T;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.5	M;M;M;M
PhyloP100		4.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-7.6	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.055	T;T;T;D
Polyphen		0.99	D;D;D;D
Vest4		0.76
MutPred		0.42		Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);Loss of glycosylation at P41 (P = 0.0038);
MVP		0.92
MPC		0.74
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		0.15	Neutral
Varity_R		0.81
gMVP		0.95
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs2125328927; hg19: chr3-9976258;