chr3-9943989-T-G

Variant names:

• chr3-9943989-T-G
• rs73118372
• ENST00000326434.9:c.1136T>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001374317.1(CRELD1):​c.1148T>G​(p.Met383Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000376 in 1,036,330 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M383T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CRELD1 NM_001374317.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.304
• Publications: 9 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03431061).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000145 (22/152034) while in subpopulation AMR AF = 0.00144 (22/15266). AF 95% confidence interval is 0.000976. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001374317.1. 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.1049-376T>G		intron	N/A	NP_001070883.2	Q96HD1-1
	CRELD1	NM_001374317.1		c.1148T>G	p.Met383Arg	missense	Exon 11 of 12	NP_001361246.1	A0A804HJJ0
	CRELD1	NM_001374318.1		c.1148T>G	p.Met383Arg	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.1136T>G	p.Met379Arg	missense	Exon 11 of 12	ENSP00000321856.5	Q96HD1-2
	CRELD1	ENST00000452070.6	TSL:2 MANE Select	c.1049-376T>G		intron	N/A	ENSP00000393643.2	Q96HD1-1
	CRELD1	ENST00000383811.8	TSL:1	c.1049-376T>G		intron	N/A	ENSP00000373322.3	Q96HD1-1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152034 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000683 AC: 17 AN: 249054 AF XY: 0.0000742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 17 AN: 884296 Hom.: 0 Cov.: 13 AF XY: 0.0000216 AC XY: 10 AN XY: 463536

African (AFR) AF: 0.00 AC: 0 AN: 22698

American (AMR) AF: 0.000386 AC: 17 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22544

East Asian (EAS) AF: 0.00 AC: 0 AN: 37038

South Asian (SAS) AF: 0.00 AC: 0 AN: 74838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 583780

Other (OTH) AF: 0.00 AC: 0 AN: 41546

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152034 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74240

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00144 AC: 22 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 637

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.4
DANN	Benign	0.62
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.30
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.049
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.032	D
Polyphen		0.0	B
Vest4		0.21
MutPred		0.46		Gain of glycosylation at Y376 (P = 0.0023)
MVP		0.17
MPC		0.24
ClinPred		0.045	T
GERP RS		1.7
gMVP		0.74
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs73118372; hg19: chr3-9985673;