rs72659357

Variant names:

• chr3-33114080-G-A
• rs72659357
• NM_006371.5:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_006371.5(CRTAP):​c.3G>A​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002766320: Authors of this study also analyzed patient derived cells, and reported that the father of the infant, whose variant alters the start codon, produced both normal and a smaller size CRTAP protein, suggesting that his cells contain a truncated form of CRTAP (likely initiated at the next methionine codon, Met42), and although they could not detect the truncated form in the infant, collagen prolyl 3-hydroxylation measurements suggested that the infant had some residual enzyme activity, supposedly derived from the paternal allele (Barnes_2006).".

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000023 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRTAP NM_006371.5 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.833
• Publications: 2 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 18 pathogenic variants. Next in-frame start position is after 42 codons. Genomic position: 33114201. Lost 0.103 part of the original CDS.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002766320: Authors of this study also analyzed patient derived cells, and reported that the father of the infant, whose variant alters the start codon, produced both normal and a smaller size CRTAP protein, suggesting that his cells contain a truncated form of CRTAP (likely initiated at the next methionine codon, Met42), and although they could not detect the truncated form in the infant, collagen prolyl 3-hydroxylation measurements suggested that the infant had some residual enzyme activity, supposedly derived from the paternal allele (Barnes_2006).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-33114080-G-A is Pathogenic according to our data. Variant chr3-33114080-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3G>A	p.Met1?	start_lost	Exon 1 of 7	NP_006362.1	O75718
	CRTAP	NM_001393363.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.3G>A	p.Met1?	start_lost	Exon 1 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.3G>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000323696.5	O75718
	CRTAP	ENST00000946650.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000230 AC: 3 AN: 1306822 Hom.: 0 Cov.: 31 AF XY: 0.00000310 AC XY: 2 AN XY: 645182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 23544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22546

East Asian (EAS) AF: 0.00 AC: 0 AN: 28468

South Asian (SAS) AF: 0.00 AC: 0 AN: 70730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4446

European-Non Finnish (NFE) AF: 0.00000287 AC: 3 AN: 1044236

Other (OTH) AF: 0.00 AC: 0 AN: 54008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Osteogenesis imperfecta type 7 (2)
1	-	-	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.74	T
PhyloP100		0.83
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.39	B
Vest4		0.84
MutPred		0.59		Loss of glycosylation at P3 (P = 0.0312)
MVP		0.66
ClinPred		0.99	D
GERP RS		3.1
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.92
gMVP		0.73
Mutation Taster		=11/189	disease causing (ClinVar)

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: rs72659357; hg19: chr3-33155572;