3-33146339-C-T

Variant names:

• chr3-33146339-C-T
• rs4678478
• NM_006371.5:c.*3891C>T

Variant summary

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

The NM_006371.5(CRTAP):​c.*3891C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,290 control chromosomes in the GnomAD database, including 5,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5051 hom., cov: 33)
  • Exomes 𝑓: 0.21 (3 hom.)
• Consequence: CRTAP NM_006371.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0330
• 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: 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

ENSG00000272149 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-33146339-C-T is Benign according to our data. Variant chr3-33146339-C-T is described in ClinVar as Benign. ClinVar VariationId is 344875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.521 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.*3891C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000320954.11	NP_006362.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.*3891C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_006371.5	ENSP00000323696.5
ENSG00000272149	ENST00000607832.1	n.166+1217G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35201 AN: 152034 Hom.: 5056 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.210 AC: 29 AN: 138 Hom.: 3 Cov.: 0 AF XY: 0.192 AC XY: 20 AN XY: 104

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.500 AC: 3 AN: 6

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.250 AC: 1 AN: 4

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.186 AC: 19 AN: 102

Other (OTH) AF: 0.188 AC: 3 AN: 16

GnomAD4 genome AF: 0.232 AC: 35225 AN: 152152 Hom.: 5051 Cov.: 33 AF XY: 0.244 AC XY: 18167 AN XY: 74374

African (AFR) AF: 0.104 AC: 4340 AN: 41542

American (AMR) AF: 0.367 AC: 5604 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3470

East Asian (EAS) AF: 0.538 AC: 2769 AN: 5146

South Asian (SAS) AF: 0.329 AC: 1584 AN: 4816

European-Finnish (FIN) AF: 0.380 AC: 4012 AN: 10566

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15604 AN: 68012

Other (OTH) AF: 0.209 AC: 442 AN: 2110

Alfa AF: 0.215 Hom.: 4996

Bravo AF: 0.224

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteogenesis imperfecta type 7 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.6
DANN	Benign	0.80
PhyloP100		0.033
Mutation Taster		=100/0	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: rs4678478; hg19: chr3-33187831;