3-9937549-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001077415.3(CRELD1):c.258-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,593,490 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (12 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (54 hom.)
• Consequence: CRELD1 NM_001077415.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0540

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-9937549-C-A is Benign according to our data. Variant chr3-9937549-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1605652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00223 (340/152210) while in subpopulation EAS AF= 0.0507 (262/5170). AF 95% confidence interval is 0.0456. There are 12 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRELD1	NM_001077415.3	c.258-13C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000452070.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRELD1	ENST00000452070.6	c.258-13C>A		splice_polypyrimidine_tract_variant, intron_variant		2	NM_001077415.3	P1

Frequencies

GnomAD3 genomes AF: 0.00224 AC: 340 AN: 152092 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0508

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00478 AC: 1145 AN: 239292 Hom.: 19 AF XY: 0.00464 AC XY: 599 AN XY: 129030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.0523

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.0000969

Gnomad NFE exome AF: 0.000931

Gnomad OTH exome AF: 0.00276

GnomAD4 exome AF: 0.00217 AC: 3134 AN: 1441280 Hom.: 54 Cov.: 29 AF XY: 0.00227 AC XY: 1631 AN XY: 717162

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000460

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0501

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.000170

Gnomad4 NFE exome AF: 0.000622

Gnomad4 OTH exome AF: 0.00241

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152210 Hom.: 12 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74400

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0507

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00106 Hom.: 0

Bravo AF: 0.00298

Asia WGS AF: 0.0170 AC: 60 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrioventricular septal defect, susceptibility to, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 17, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.7
Dann	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs117956843; hg19: chr3-9979233; COSMIC: COSV55975100; COSMIC: COSV55975100;