rs146124454

Variant names:

• chr3-33124427-T-C
• rs146124454
• NM_006371.5:c.641T>C

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: 6.15
• Publications: 5 publications found

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]

CRTAP Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 7

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 284535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006371.5. 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
	CRTAP	NM_006371.5	MANE Select	c.641T>C	p.Val214Ala	missense	Exon 3 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.641T>C	p.Val214Ala	missense	Exon 3 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.641T>C	p.Val214Ala	missense	Exon 3 of 6	NP_001380293.1	C9JP16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.641T>C	p.Val214Ala	missense	Exon 3 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.674T>C	p.Val225Ala	missense	Exon 3 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.641T>C	p.Val214Ala	missense	Exon 3 of 7	ENSP00000616707.1

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

GnomAD2 exomes AF: 0.00613 AC: 1541 AN: 251484 AF XY: 0.00796

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 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

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000880 AC: 23 AN: 26136

East Asian (EAS) AF: 0.000932 AC: 37 AN: 39700

South Asian (SAS) AF: 0.0427 AC: 3683 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00958 AC: 55 AN: 5742

European-Non Finnish (NFE) AF: 0.000507 AC: 564 AN: 1112006

Other (OTH) AF: 0.00450 AC: 272 AN: 60390

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

African (AFR) AF: 0.000433 AC: 18 AN: 41558

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5192

South Asian (SAS) AF: 0.0491 AC: 237 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00114 Hom.: 5

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Osteogenesis imperfecta type 7 (2)
-	-	1	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	-0.084	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=90/10	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: rs146124454; hg19: chr3-33165919; COSMIC: COSV58013997;