3-9943989-T-C

Variant names:

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

Variant summary

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

The ENST00000326434.9(CRELD1):​c.1136T>C​(p.Met379Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 1,036,400 control chromosomes in the GnomAD database, including 1,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M379R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.065 (939 hom., cov: 32)
  • Exomes 𝑓: 0.013 (744 hom.)
• Consequence: CRELD1 ENST00000326434.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.304
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027036965).
• BP6: Variant 3-9943989-T-C is Benign according to our data. Variant chr3-9943989-T-C is described in ClinVar as Benign. ClinVar VariationId is 137031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	NM_001077415.3	MANE Select	c.1049-376T>C		intron	N/A	NP_001070883.2
	CRELD1	NM_001374317.1		c.1148T>C	p.Met383Thr	missense	Exon 11 of 12	NP_001361246.1
	CRELD1	NM_001374318.1		c.1148T>C	p.Met383Thr	missense	Exon 10 of 11	NP_001361247.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRELD1	ENST00000326434.9	TSL:1	c.1136T>C	p.Met379Thr	missense	Exon 11 of 12	ENSP00000321856.5
	CRELD1	ENST00000452070.6	TSL:2 MANE Select	c.1049-376T>C		intron	N/A	ENSP00000393643.2
	CRELD1	ENST00000383811.8	TSL:1	c.1049-376T>C		intron	N/A	ENSP00000373322.3

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9880 AN: 152004 Hom.: 933 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0484

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.0512

GnomAD2 exomes AF: 0.0264 AC: 6568 AN: 249054 AF XY: 0.0229

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0303

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0253

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0134 AC: 11835 AN: 884278 Hom.: 744 Cov.: 13 AF XY: 0.0133 AC XY: 6162 AN XY: 463528

African (AFR) AF: 0.229 AC: 5200 AN: 22680

American (AMR) AF: 0.0312 AC: 1371 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.0000444 AC: 1 AN: 22544

East Asian (EAS) AF: 0.0208 AC: 770 AN: 37038

South Asian (SAS) AF: 0.0406 AC: 3036 AN: 74838

European-Finnish (FIN) AF: 0.000207 AC: 11 AN: 53226

Middle Eastern (MID) AF: 0.0323 AC: 149 AN: 4614

European-Non Finnish (NFE) AF: 0.000625 AC: 365 AN: 583780

Other (OTH) AF: 0.0224 AC: 932 AN: 41546

GnomAD4 genome AF: 0.0652 AC: 9917 AN: 152122 Hom.: 939 Cov.: 32 AF XY: 0.0631 AC XY: 4689 AN XY: 74356

African (AFR) AF: 0.215 AC: 8932 AN: 41464

American (AMR) AF: 0.0293 AC: 448 AN: 15286

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

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5178

South Asian (SAS) AF: 0.0479 AC: 231 AN: 4826

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

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68004

Other (OTH) AF: 0.0526 AC: 111 AN: 2110

Alfa AF: 0.0210 Hom.: 637

Bravo AF: 0.0748

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.210 AC: 927

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0297 AC: 3608

Asia WGS AF: 0.0350 AC: 123 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Oct 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Atrioventricular septal defect, susceptibility to, 2 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	2.7
DANN	Benign	0.53
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.18	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.30
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.051
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.027
MPC		0.18
ClinPred		0.000023	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.49
Mutation Taster		=100/0	polymorphism (auto)

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: rs73118372; hg19: chr3-9985673; COSMIC: COSV107353565; COSMIC: COSV107353565;