chr17-5433172-G-T

Variant names:

• chr17-5433172-G-T
• rs185497470
• NM_001212.4:c.700-8C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001212.4(C1QBP):​c.700-8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,610,432 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (27 hom.)
• Consequence: C1QBP NM_001212.4 splice_region, intron
• Scores: Splicing: ADA: 0.002874
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.839
• Publications: 0 publications found

Genes affected

C1QBP (HGNC:1243): (complement C1q binding protein) The human complement subcomponent C1q associates with C1r and C1s in order to yield the first component of the serum complement system. The protein encoded by this gene is known to bind to the globular heads of C1q molecules and inhibit C1 activation. This protein has also been identified as the p32 subunit of pre-mRNA splicing factor SF2, as well as a hyaluronic acid-binding protein. [provided by RefSeq, Jul 2008]

C1QBP Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• combined oxidative phosphorylation deficiency 33

  Inheritance: AR Classification: STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-5433172-G-T is Benign according to our data. Variant chr17-5433172-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 711527.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 = 0.00443 (674/152172) while in subpopulation NFE AF = 0.00647 (440/67992). AF 95% confidence interval is 0.00597. There are 4 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001212.4. 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
	C1QBP	NM_001212.4	MANE Select	c.700-8C>A		splice_region intron	N/A	NP_001203.1	Q07021

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QBP	ENST00000225698.8	TSL:1 MANE Select	c.700-8C>A		splice_region intron	N/A	ENSP00000225698.4	Q07021
	C1QBP	ENST00000574444.5	TSL:3	c.388-8C>A		splice_region intron	N/A	ENSP00000460308.1	I3L3B0
	C1QBP	ENST00000570805.1	TSL:3	c.388-8C>A		splice_region intron	N/A	ENSP00000460638.1	I3L3Q7

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 675 AN: 152054 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00840

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00647

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00482 AC: 1189 AN: 246870 AF XY: 0.00482

Gnomad AFR exome AF: 0.000824

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00677

Gnomad NFE exome AF: 0.00648

Gnomad OTH exome AF: 0.00533

GnomAD4 exome AF: 0.00527 AC: 7692 AN: 1458260 Hom.: 27 Cov.: 31 AF XY: 0.00527 AC XY: 3823 AN XY: 725434

African (AFR) AF: 0.00118 AC: 39 AN: 33152

American (AMR) AF: 0.00190 AC: 83 AN: 43688

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 425 AN: 25958

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.00108 AC: 92 AN: 85490

European-Finnish (FIN) AF: 0.00671 AC: 358 AN: 53374

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5742

European-Non Finnish (NFE) AF: 0.00567 AC: 6294 AN: 1110950

Other (OTH) AF: 0.00546 AC: 329 AN: 60222

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152172 Hom.: 4 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74400

African (AFR) AF: 0.000915 AC: 38 AN: 41534

American (AMR) AF: 0.00223 AC: 34 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00840 AC: 89 AN: 10590

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00647 AC: 440 AN: 67992

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00514 Hom.: 1

Bravo AF: 0.00377

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	C1QBP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.6
DANN	Benign	0.76
PhyloP100		0.84
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.010		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: rs185497470; hg19: chr17-5336492;