chr3-33124518-C-T

Position:

• chr3-33124518-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006371.5(CRTAP):​c.732C>T​(p.Leu244Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,206 control chromosomes in the GnomAD database, including 3 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 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (3 hom.)
• Consequence: CRTAP NM_006371.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -4.21

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-33124518-C-T is Benign according to our data. Variant chr3-33124518-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284911.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=1}. Variant chr3-33124518-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (266/152318) while in subpopulation NFE AF= 0.00309 (210/68036). AF 95% confidence interval is 0.00274. There are 0 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTAP	NM_006371.5	c.732C>T	p.Leu244Leu	synonymous_variant	3/7	ENST00000320954.11	NP_006362.1
CRTAP	NM_001393363.1	c.732C>T	p.Leu244Leu	synonymous_variant	3/6		NP_001380292.1
CRTAP	NM_001393364.1	c.732C>T	p.Leu244Leu	synonymous_variant	3/6		NP_001380293.1
CRTAP	NM_001393365.1	c.582C>T	p.Leu194Leu	synonymous_variant	2/6		NP_001380294.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRTAP	ENST00000320954.11	c.732C>T	p.Leu244Leu	synonymous_variant	3/7	1	NM_006371.5	ENSP00000323696.5
CRTAP	ENST00000449224.1	c.732C>T	p.Leu244Leu	synonymous_variant	3/6	2		ENSP00000409997.1
CRTAP	ENST00000485310.1	n.326C>T		non_coding_transcript_exon_variant	3/5	4

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00213 AC: 535 AN: 251478 Hom.: 0 AF XY: 0.00196 AC XY: 266 AN XY: 135916

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00271 AC: 3963 AN: 1461888 Hom.: 3 Cov.: 31 AF XY: 0.00257 AC XY: 1868 AN XY: 727246

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.00173 AC XY: 129 AN XY: 74490

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00309

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00181

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00243

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta type 7 Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CRTAP: BP4, BP7 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 07, 2015

- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 19, 2022

- -

CRTAP-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.13
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs149119710; hg19: chr3-33166010;