13-24321346-G-C

Variant names:

• chr13-24321346-G-C
• rs371292590
• NM_178540.5:c.580G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_178540.5(C1QTNF9):​c.580G>C​(p.Gly194Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. G194S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 19)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: C1QTNF9 NM_178540.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.54
• Publications: 2 publications found

Genes affected

C1QTNF9 (HGNC:28732): (C1q and TNF related 9) Enables identical protein binding activity. Predicted to be involved in signal transduction. Predicted to be located in extracellular region. Predicted to be part of collagen trimer. [provided by Alliance of Genome Resources, Apr 2022]

PCOTHP1 (HGNC:39840):

C1QTNF9-AS1 (HGNC:39906): (C1QTNF9 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178540.5. 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
	C1QTNF9	NM_178540.5	MANE Select	c.580G>C	p.Gly194Arg	missense	Exon 4 of 4	NP_848635.2	P0C862
	C1QTNF9	NM_001303137.2		c.580G>C	p.Gly194Arg	missense	Exon 5 of 5	NP_001290066.1	P0C862
	C1QTNF9	NM_001303138.2		c.580G>C	p.Gly194Arg	missense	Exon 4 of 4	NP_001290067.1	P0C862

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1QTNF9	ENST00000332018.5	TSL:1 MANE Select	c.580G>C	p.Gly194Arg	missense	Exon 4 of 4	ENSP00000333737.4	P0C862
	C1QTNF9	ENST00000382071.6	TSL:5	c.580G>C	p.Gly194Arg	missense	Exon 4 of 4	ENSP00000371503.2	P0C862
	C1QTNF9	ENST00000875261.1		c.580G>C	p.Gly194Arg	missense	Exon 5 of 5	ENSP00000545320.1

Frequencies

GnomAD3 genomes AF: 0.00000707 AC: 1 AN: 141392 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000815 AC: 2 AN: 245412 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000903

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456592 Hom.: 0 Cov.: 35 AF XY: 0.00000276 AC XY: 2 AN XY: 724102

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.0000224 AC: 1 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108232

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000707 AC: 1 AN: 141392 Hom.: 0 Cov.: 19 AF XY: 0.0000147 AC XY: 1 AN XY: 68020

African (AFR) AF: 0.0000254 AC: 1 AN: 39328

American (AMR) AF: 0.00 AC: 0 AN: 13486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3308

East Asian (EAS) AF: 0.00 AC: 0 AN: 4856

South Asian (SAS) AF: 0.00 AC: 0 AN: 4132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 64568

Other (OTH) AF: 0.00 AC: 0 AN: 1866

Alfa AF: 0.0000434 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.5
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.65		Gain of catalytic residue at L197 (P = 0.0034)
MVP		0.94
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.93
gMVP		0.93
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371292590; hg19: chr13-24895484;