rs146124454

chr3-33124427-T-C

Variant summary

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

The NM_006371.5(CRTAP):c.641T>C(p.Val214Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00311 in 1,614,160 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (125 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.15

Genes affected

CRTAP (HGNC:2379): (cartilage associated protein) The protein encoded by this gene is similar to the chicken and mouse CRTAP genes. The encoded protein is a scaffolding protein that may influence the activity of at least one member of the cytohesin/ARNO family in response to specific cellular stimuli. Defects in this gene are associated with osteogenesis imperfecta, a connective tissue disorder characterized by bone fragility and low bone mass. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0097948015).
• BP6: Variant 3-33124427-T-C is Benign according to our data. Variant chr3-33124427-T-C is described in ClinVar as [Benign]. Clinvar id is 284535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33124427-T-C is described in Lovd as [Likely_benign]. Variant chr3-33124427-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00218 (332/152308) while in subpopulation SAS AF= 0.0491 (237/4826). AF 95% confidence interval is 0.044. There are 7 homozygotes in gnomad4. There are 216 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.641T>C	p.Val214Ala	missense_variant	3/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.641T>C	p.Val214Ala	missense_variant	3/6
CRTAP	NM_001393364.1	c.641T>C	p.Val214Ala	missense_variant	3/6
CRTAP	NM_001393365.1	c.491T>C	p.Val164Ala	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.641T>C	p.Val214Ala	missense_variant	3/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.641T>C	p.Val214Ala	missense_variant	3/6	2
CRTAP	ENST00000485310.1	n.235T>C		non_coding_transcript_exon_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.00217 AC: 331 AN: 152190 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00211

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00613 AC: 1541 AN: 251484 Hom.: 42 AF XY: 0.00796 AC XY: 1082 AN XY: 135918

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.0444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000747

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00320 AC: 4683 AN: 1461852 Hom.: 125 Cov.: 31 AF XY: 0.00438 AC XY: 3185 AN XY: 727224

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.000932

Gnomad4 SAS exome AF: 0.0427

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.00450

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152308 Hom.: 7 Cov.: 33 AF XY: 0.00290 AC XY: 216 AN XY: 74488

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.0491

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000865 Hom.: 1

Bravo AF: 0.000880

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00694 AC: 842

Asia WGS AF: 0.0350 AC: 121 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Osteogenesis imperfecta type 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 25, 2022

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D;D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.76
MVP		0.74
MPC		0.27
ClinPred		0.024	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs146124454; hg19: chr3-33165919; COSMIC: COSV58013997;