NM_006371.5:c.534C>T

Variant names:

• chr3-33120406-C-T
• rs4076086
• NM_006371.5:c.534C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_006371.5(CRTAP):​c.534C>T​(p.Asp178Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,613,334 control chromosomes in the GnomAD database, including 20,994 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3785 hom., cov: 32)
  • Exomes 𝑓: 0.12 (17209 hom.)
• Consequence: CRTAP NM_006371.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.934
• Publications: 31 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 3-33120406-C-T is Benign according to our data. Variant chr3-33120406-C-T is described in ClinVar as Benign. ClinVar VariationId is 195265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.934 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	NM_006371.5	MANE Select	c.534C>T	p.Asp178Asp	synonymous	Exon 2 of 7	NP_006362.1
	CRTAP	NM_001393363.1		c.534C>T	p.Asp178Asp	synonymous	Exon 2 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.534C>T	p.Asp178Asp	synonymous	Exon 2 of 6	NP_001380293.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.534C>T	p.Asp178Asp	synonymous	Exon 2 of 7	ENSP00000323696.5
	CRTAP	ENST00000449224.1	TSL:2	c.534C>T	p.Asp178Asp	synonymous	Exon 2 of 6	ENSP00000409997.1
	CRTAP	ENST00000485310.1	TSL:4	n.128C>T		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27912 AN: 151982 Hom.: 3770 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.166

Gnomad NFE AF: 0.0874

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.172 AC: 42717 AN: 249034 AF XY: 0.164

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.582

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.0872

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.120 AC: 174656 AN: 1461234 Hom.: 17209 Cov.: 32 AF XY: 0.120 AC XY: 87515 AN XY: 726954

African (AFR) AF: 0.322 AC: 10776 AN: 33452

American (AMR) AF: 0.156 AC: 6976 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 3065 AN: 26134

East Asian (EAS) AF: 0.606 AC: 24060 AN: 39686

South Asian (SAS) AF: 0.180 AC: 15552 AN: 86236

European-Finnish (FIN) AF: 0.185 AC: 9906 AN: 53420

Middle Eastern (MID) AF: 0.124 AC: 712 AN: 5762

European-Non Finnish (NFE) AF: 0.0856 AC: 95115 AN: 1111462

Other (OTH) AF: 0.141 AC: 8494 AN: 60358

GnomAD4 genome AF: 0.184 AC: 27973 AN: 152100 Hom.: 3785 Cov.: 32 AF XY: 0.191 AC XY: 14218 AN XY: 74348

African (AFR) AF: 0.317 AC: 13149 AN: 41472

American (AMR) AF: 0.131 AC: 1997 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 402 AN: 3470

East Asian (EAS) AF: 0.579 AC: 2998 AN: 5176

South Asian (SAS) AF: 0.204 AC: 984 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2056 AN: 10560

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.0874 AC: 5944 AN: 68010

Other (OTH) AF: 0.161 AC: 340 AN: 2110

Alfa AF: 0.122 Hom.: 7585

Bravo AF: 0.189

Asia WGS AF: 0.350 AC: 1216 AN: 3478

EpiCase AF: 0.0885

EpiControl AF: 0.0843

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.34
DANN	Benign	0.46
PhyloP100		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism (auto)

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: rs4076086; hg19: chr3-33161898; COSMIC: COSV58013030;