rs202118861

Positions:

• chr3-33114528-C-G
• chr3-33114528-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM5 BS1_Supporting BS2

The NM_006371.5(CRTAP):​c.451C>G​(p.Leu151Val) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,602,454 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L151P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00069 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: CRTAP NM_006371.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 3.79

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-33114529-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1510318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152358) while in subpopulation NFE AF= 0.00123 (84/68032). AF 95% confidence interval is 0.00102. There are 1 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTAP	NM_006371.5	c.451C>G	p.Leu151Val	missense_variant	1/7	ENST00000320954.11
CRTAP	NM_001393363.1	c.451C>G	p.Leu151Val	missense_variant	1/6
CRTAP	NM_001393364.1	c.451C>G	p.Leu151Val	missense_variant	1/6
CRTAP	NM_001393365.1	c.451C>G	p.Leu151Val	missense_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTAP	ENST00000320954.11	c.451C>G	p.Leu151Val	missense_variant	1/7	1	NM_006371.5	P1
CRTAP	ENST00000449224.1	c.451C>G	p.Leu151Val	missense_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152244 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000529 AC: 114 AN: 215494 Hom.: 0 AF XY: 0.000504 AC XY: 60 AN XY: 119164

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000974

Gnomad OTH exome AF: 0.000564

GnomAD4 exome AF: 0.00130 AC: 1890 AN: 1450096 Hom.: 5 Cov.: 32 AF XY: 0.00123 AC XY: 883 AN XY: 720512

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000729

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152358 Hom.: 1 Cov.: 34 AF XY: 0.000685 AC XY: 51 AN XY: 74502

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00123

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.000820

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ExAC AF: 0.000368 AC: 42

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 7 Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2022	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 151 of the CRTAP protein (p.Leu151Val). This variant is present in population databases (rs202118861, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CRTAP-related conditions. ClinVar contains an entry for this variant (Variation ID: 429858). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CRTAP protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 11, 2019	The CRTAP c.451C>G; p.Leu151Val variant (rs202118861), to our knowledge, has not been described in the medical literature but is listed as a variant of uncertain significance in ClinVar (Variation ID: 429858). It is observed in the general population at an overall frequency of 0.053% (131/246878 alleles) in the Genome Aggregation Database. The leucine at codon 151 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Another variant at this codon position (c.452T>C; p.Leu151Pro) has been described homozygously in an individual affected with osteogenesis imperfect type 3, though it is unclear if this variant was causative for the phenotype in this patient (Caparros-Martin 2016). Due to limited information regarding the p.Leu151Val variant, its clinical significance cannot be determined with certainty. REFERENCES Caparros-Martin J et al. Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. Mol Genet Genomic Med. 2016 Dec 20;5(1):28-39. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
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. -

Osteogenesis imperfecta Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.84
MVP		0.65
MPC		0.54
ClinPred		0.11	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs202118861; hg19: chr3-33156020;