rs279552

Variant names:

• chr3-9934475-A-G
• rs279552
• NM_001077415.3:c.37A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001077415.3(CRELD1):​c.37A>G​(p.Met13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,613,982 control chromosomes in the GnomAD database, including 790,642 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74939 hom., cov: 30)
  • Exomes 𝑓: 0.99 (715703 hom.)
• Consequence: CRELD1 NM_001077415.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.403
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.5156565E-7).
• BP6: Variant 3-9934475-A-G is Benign according to our data. Variant chr3-9934475-A-G is described in ClinVar as Benign. ClinVar VariationId is 1164100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077415.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	NM_001077415.3	MANE Select	c.37A>G	p.Met13Val	missense	Exon 2 of 11	NP_001070883.2
	CRELD1	NM_001374317.1		c.37A>G	p.Met13Val	missense	Exon 2 of 12	NP_001361246.1
	CRELD1	NM_001374318.1		c.37A>G	p.Met13Val	missense	Exon 1 of 11	NP_001361247.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	ENST00000452070.6	TSL:2 MANE Select	c.37A>G	p.Met13Val	missense	Exon 2 of 11	ENSP00000393643.2
	CRELD1	ENST00000326434.9	TSL:1	c.37A>G	p.Met13Val	missense	Exon 2 of 12	ENSP00000321856.5
	CRELD1	ENST00000383811.8	TSL:1	c.37A>G	p.Met13Val	missense	Exon 1 of 10	ENSP00000373322.3

Frequencies

GnomAD3 genomes AF: 0.992 AC: 150936 AN: 152132 Hom.: 74878 Cov.: 30

Gnomad AFR AF: 0.998

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.988

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.990

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.988

Gnomad OTH AF: 0.990

GnomAD2 exomes AF: 0.991 AC: 249146 AN: 251350 AF XY: 0.991

Gnomad AFR exome AF: 0.998

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.990

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.988

Gnomad OTH exome AF: 0.992

GnomAD4 exome AF: 0.990 AC: 1446473 AN: 1461732 Hom.: 715703 Cov.: 55 AF XY: 0.990 AC XY: 719552 AN XY: 727168

African (AFR) AF: 0.998 AC: 33417 AN: 33476

American (AMR) AF: 0.993 AC: 44399 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 25845 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 0.989 AC: 85303 AN: 86254

European-Finnish (FIN) AF: 0.997 AC: 53186 AN: 53344

Middle Eastern (MID) AF: 0.990 AC: 5710 AN: 5768

European-Non Finnish (NFE) AF: 0.988 AC: 1099081 AN: 1111944

Other (OTH) AF: 0.991 AC: 59834 AN: 60388

GnomAD4 genome AF: 0.992 AC: 151056 AN: 152250 Hom.: 74939 Cov.: 30 AF XY: 0.992 AC XY: 73843 AN XY: 74428

African (AFR) AF: 0.998 AC: 41466 AN: 41556

American (AMR) AF: 0.991 AC: 15139 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 3432 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5165 AN: 5166

South Asian (SAS) AF: 0.990 AC: 4783 AN: 4830

European-Finnish (FIN) AF: 0.998 AC: 10581 AN: 10602

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.988 AC: 67194 AN: 68026

Other (OTH) AF: 0.991 AC: 2090 AN: 2110

Alfa AF: 0.990 Hom.: 243417

Bravo AF: 0.992

TwinsUK AF: 0.989 AC: 3669

ALSPAC AF: 0.991 AC: 3818

ESP6500AA AF: 0.998 AC: 4399

ESP6500EA AF: 0.988 AC: 8496

ExAC AF: 0.992 AC: 120388

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 0.987

EpiControl AF: 0.988

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Atrioventricular septal defect, susceptibility to, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.6
DANN	Benign	0.68
DEOGEN2	Benign	0.00068	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	9.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.40
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.064
Sift	Benign	0.55	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.061
MPC		0.16
ClinPred		0.0013	T
GERP RS		0.33
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.032
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs279552; hg19: chr3-9976159; COSMIC: COSV99925630; COSMIC: COSV99925630;