rs115198029

Variant names:

• chr3-33132671-C-T
• rs115198029
• NM_006371.5:c.1039C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006371.5(CRTAP):​c.1039C>T​(p.Leu347Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,614,124 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (10 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 7.80
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022593439).
• BP6: Variant 3-33132671-C-T is Benign according to our data. Variant chr3-33132671-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439559.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00247 (376/152312) while in subpopulation AMR AF = 0.00497 (76/15300). AF 95% confidence interval is 0.00407. There are 0 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.1039C>T	p.Leu347Phe	missense	Exon 5 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.1039C>T	p.Leu347Phe	missense	Exon 5 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.910C>T	p.Leu304Phe	missense	Exon 4 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.1039C>T	p.Leu347Phe	missense	Exon 5 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.1072C>T	p.Leu358Phe	missense	Exon 5 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.1039C>T	p.Leu347Phe	missense	Exon 5 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00367

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00201 AC: 506 AN: 251494 AF XY: 0.00200

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00285

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00312 AC: 4557 AN: 1461812 Hom.: 10 Cov.: 40 AF XY: 0.00303 AC XY: 2207 AN XY: 727222

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00396 AC: 177 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53416

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.00371 AC: 4123 AN: 1111962

Other (OTH) AF: 0.00275 AC: 166 AN: 60392

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74480

African (AFR) AF: 0.000722 AC: 30 AN: 41564

American (AMR) AF: 0.00497 AC: 76 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00367 AC: 250 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00196 Hom.: 64

Bravo AF: 0.00227

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00180 AC: 219

EpiCase AF: 0.00354

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.79
MPC		0.57
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.59
gMVP		0.50
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs115198029; hg19: chr3-33174163; COSMIC: COSV105211586; COSMIC: COSV105211586;