ENST00000326434.9:c.1123A>G

Variant names:

• chr3-9943976-A-G
• rs920334740
• ENST00000326434.9:c.1123A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000326434.9(CRELD1):​c.1123A>G​(p.Thr375Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000926 in 1,079,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T375T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: CRELD1 ENST00000326434.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.409
• 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]

ENSG00000288550 (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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05924523).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326434.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	NM_001077415.3	MANE Select	c.1049-389A>G		intron	N/A	NP_001070883.2	Q96HD1-1
	CRELD1	NM_001374317.1		c.1135A>G	p.Thr379Ala	missense	Exon 11 of 12	NP_001361246.1	A0A804HJJ0
	CRELD1	NM_001374318.1		c.1135A>G	p.Thr379Ala	missense	Exon 10 of 11	NP_001361247.1	A0A804HJJ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	ENST00000326434.9	TSL:1	c.1123A>G	p.Thr375Ala	missense	Exon 11 of 12	ENSP00000321856.5	Q96HD1-2
	CRELD1	ENST00000452070.6	TSL:2 MANE Select	c.1049-389A>G		intron	N/A	ENSP00000393643.2	Q96HD1-1
	CRELD1	ENST00000383811.8	TSL:1	c.1049-389A>G		intron	N/A	ENSP00000373322.3	Q96HD1-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249054 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000862 AC: 8 AN: 927624 Hom.: 0 Cov.: 13 AF XY: 0.00000620 AC XY: 3 AN XY: 483690

African (AFR) AF: 0.00 AC: 0 AN: 23178

American (AMR) AF: 0.000136 AC: 6 AN: 44074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22804

East Asian (EAS) AF: 0.00 AC: 0 AN: 37302

South Asian (SAS) AF: 0.00 AC: 0 AN: 75514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4714

European-Non Finnish (NFE) AF: 0.00000321 AC: 2 AN: 623788

Other (OTH) AF: 0.00 AC: 0 AN: 43014

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.000131 AC: 2 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Atrioventricular septal defect, susceptibility to, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.79
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.41
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.075
Sift	Benign	0.13	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.51		Gain of glycosylation at Y376 (P = 0.0023)
MVP		0.26
MPC		0.16
ClinPred		0.028	T
GERP RS		-0.066
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.34
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs920334740; hg19: chr3-9985660;