rs3751353

Variant names:

• chr13-24320996-G-C
• rs3751353
• NM_178540.5:c.230G>C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

The NM_178540.5(C1QTNF9):​c.230G>C​(p.Gly77Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,585,650 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0028 (11 hom., cov: 23)
  • Exomes 𝑓: 0.0025 (127 hom.)
• Consequence: C1QTNF9 NM_178540.5 missense, splice_region
• Scores: Splicing: ADA: 0.9962
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.70

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]

ENSG00000273167 (HGNC:):

PCOTHP1 (HGNC:39840):

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

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1QTNF9	NM_178540.5	c.230G>C	p.Gly77Ala	missense_variant, splice_region_variant	Exon 4 of 4	ENST00000332018.5	NP_848635.2
C1QTNF9	NM_001303137.2	c.230G>C	p.Gly77Ala	missense_variant, splice_region_variant	Exon 5 of 5		NP_001290066.1
C1QTNF9	NM_001303138.2	c.230G>C	p.Gly77Ala	missense_variant, splice_region_variant	Exon 4 of 4		NP_001290067.1
PCOTHP1		n.24320996G>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1QTNF9	ENST00000332018.5	c.230G>C	p.Gly77Ala	missense_variant, splice_region_variant	Exon 4 of 4	1	NM_178540.5	ENSP00000333737.4
ENSG00000273167	ENST00000382141.4	n.*226G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 16	5		ENSP00000371576.4
ENSG00000273167	ENST00000382141.4	n.*226G>C		3_prime_UTR_variant	Exon 16 of 16	5		ENSP00000371576.4

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 412 AN: 148968 Hom.: 11 Cov.: 23

Gnomad AFR AF: 0.000616

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.000873

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00350

GnomAD3 exomes AF: 0.00915 AC: 2104 AN: 229946 Hom.: 72 AF XY: 0.00710 AC XY: 887 AN XY: 125016

Gnomad AFR exome AF: 0.000783

Gnomad AMR exome AF: 0.0618

Gnomad ASJ exome AF: 0.000356

Gnomad EAS exome AF: 0.0113

Gnomad SAS exome AF: 0.000265

Gnomad FIN exome AF: 0.0000949

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.00513

GnomAD4 exome AF: 0.00249 AC: 3581 AN: 1436572 Hom.: 127 Cov.: 30 AF XY: 0.00217 AC XY: 1552 AN XY: 714418

Gnomad4 AFR exome AF: 0.000403

Gnomad4 AMR exome AF: 0.0577

Gnomad4 ASJ exome AF: 0.000328

Gnomad4 EAS exome AF: 0.0287

Gnomad4 SAS exome AF: 0.000196

Gnomad4 FIN exome AF: 0.0000949

Gnomad4 NFE exome AF: 0.000107

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00277 AC: 413 AN: 149078 Hom.: 11 Cov.: 23 AF XY: 0.00291 AC XY: 211 AN XY: 72496

Gnomad4 AFR AF: 0.000615

Gnomad4 AMR AF: 0.0198

Gnomad4 ASJ AF: 0.000873

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000164

Gnomad4 OTH AF: 0.00346

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00551

ESP6500AA AF: 0.000913 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00734 AC: 891

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	.;D
MetaRNN	Benign	0.0077	T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.78	P;P
Vest4		0.63
MVP		0.92
ClinPred		0.086	T
GERP RS		4.1
Varity_R		0.89
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3751353; hg19: chr13-24895134;