NM_006371.5:c.558A>G

Variant names:

• chr3-33120430-A-G
• rs35357409
• NM_006371.5:c.558A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006371.5(CRTAP):​c.558A>G​(p.Ala186Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,613,268 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A186A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (171 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (180 hom.)
• Consequence: CRTAP NM_006371.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.14
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-33120430-A-G is Benign according to our data. Variant chr3-33120430-A-G is described in ClinVar as Benign. ClinVar VariationId is 195266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0904 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	NM_006371.5	MANE Select	c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 7	NP_006362.1
	CRTAP	NM_001393363.1		c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 6	NP_001380292.1
	CRTAP	NM_001393364.1		c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 6	NP_001380293.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRTAP	ENST00000320954.11	TSL:1 MANE Select	c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 7	ENSP00000323696.5
	CRTAP	ENST00000946650.1		c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 7	ENSP00000616709.1
	CRTAP	ENST00000946648.1		c.558A>G	p.Ala186Ala	synonymous	Exon 2 of 7	ENSP00000616707.1

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4186 AN: 152198 Hom.: 170 Cov.: 32

Gnomad AFR AF: 0.0928

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0173

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00822 AC: 2046 AN: 249022 AF XY: 0.00605

Gnomad AFR exome AF: 0.0921

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0162

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00349 AC: 5102 AN: 1460952 Hom.: 180 Cov.: 31 AF XY: 0.00311 AC XY: 2257 AN XY: 726866

African (AFR) AF: 0.0963 AC: 3223 AN: 33454

American (AMR) AF: 0.00521 AC: 233 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.0185 AC: 736 AN: 39692

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1111176

Other (OTH) AF: 0.00784 AC: 473 AN: 60356

GnomAD4 genome AF: 0.0276 AC: 4198 AN: 152316 Hom.: 171 Cov.: 32 AF XY: 0.0264 AC XY: 1970 AN XY: 74492

African (AFR) AF: 0.0928 AC: 3857 AN: 41546

American (AMR) AF: 0.0104 AC: 159 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0173 AC: 90 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68032

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0208 Hom.: 113

Bravo AF: 0.0309

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Osteogenesis imperfecta type 7 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.027
DANN	Benign	0.45
PhyloP100		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs35357409; hg19: chr3-33161922;