13-24321346-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_178540.5(C1QTNF9):​c.580G>A​(p.Gly194Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,456,590 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. G194R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000012 (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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

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>A	p.Gly194Ser	missense	Exon 4 of 4	NP_848635.2	P0C862
	C1QTNF9	NM_001303137.2		c.580G>A	p.Gly194Ser	missense	Exon 5 of 5	NP_001290066.1	P0C862
	C1QTNF9	NM_001303138.2		c.580G>A	p.Gly194Ser	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>A	p.Gly194Ser	missense	Exon 4 of 4	ENSP00000333737.4	P0C862
	C1QTNF9	ENST00000382071.6	TSL:5	c.580G>A	p.Gly194Ser	missense	Exon 4 of 4	ENSP00000371503.2	P0C862
	C1QTNF9	ENST00000875261.1		c.580G>A	p.Gly194Ser	missense	Exon 5 of 5	ENSP00000545320.1

Frequencies

GnomAD3 genomes AF: 0.0000212 AC: 3 AN: 141392 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.0000509

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: 0.0000155

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000163 AC: 4 AN: 245412 AF XY: 0.0000150

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000271

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 17 AN: 1456590 Hom.: 0 Cov.: 35 AF XY: 0.0000138 AC XY: 10 AN XY: 724100

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000233 AC: 2 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: 0.0000117 AC: 13 AN: 1108232

Other (OTH) AF: 0.0000332 AC: 2 AN: 60240

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000212 AC: 3 AN: 141392 Hom.: 0 Cov.: 19 AF XY: 0.0000294 AC XY: 2 AN XY: 68020

African (AFR) AF: 0.0000509 AC: 2 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: 0.0000155 AC: 1 AN: 64568

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

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

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	0.071
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.096	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.028	D
Polyphen		0.90	P
Vest4		0.55
MVP		0.96
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.82
gMVP		0.87
Mutation Taster		=66/34	polymorphism

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

Other links and lift over

dbSNP: rs371292590; hg19: chr13-24895484;