rs3751353

Variant names:

• chr13-24320996-G-C
• rs3751353
• NM_178540.5:c.230G>C
• C1QTNF9 p.Gly77Ala

Variant summary

Our verdict is Benign. The variant received -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
• 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]

ENSG00000273167 (HGNC:):

PCOTHP1 (HGNC:39840):

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

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.230G>C	p.Gly77Ala	missense splice_region	Exon 4 of 4	NP_848635.2	P0C862
	C1QTNF9	NM_001303137.2		c.230G>C	p.Gly77Ala	missense splice_region	Exon 5 of 5	NP_001290066.1	P0C862
	C1QTNF9	NM_001303138.2		c.230G>C	p.Gly77Ala	missense splice_region	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.230G>C	p.Gly77Ala	missense splice_region	Exon 4 of 4	ENSP00000333737.4	P0C862
	ENSG00000273167	ENST00000382141.4	TSL:5	n.*226G>C		splice_region non_coding_transcript_exon	Exon 16 of 16	ENSP00000371576.4	A0A0A0MRY4
	ENSG00000273167	ENST00000382141.4	TSL:5	n.*226G>C		3_prime_UTR	Exon 16 of 16	ENSP00000371576.4	A0A0A0MRY4

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

GnomAD2 exomes AF: 0.00915 AC: 2104 AN: 229946 AF XY: 0.00710

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 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

African (AFR) AF: 0.000403 AC: 13 AN: 32254

American (AMR) AF: 0.0577 AC: 2201 AN: 38160

Ashkenazi Jewish (ASJ) AF: 0.000328 AC: 8 AN: 24358

East Asian (EAS) AF: 0.0287 AC: 1137 AN: 39646

South Asian (SAS) AF: 0.000196 AC: 16 AN: 81664

European-Finnish (FIN) AF: 0.0000949 AC: 5 AN: 52710

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5626

European-Non Finnish (NFE) AF: 0.000107 AC: 118 AN: 1102968

Other (OTH) AF: 0.00139 AC: 82 AN: 59186

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

African (AFR) AF: 0.000615 AC: 25 AN: 40674

American (AMR) AF: 0.0198 AC: 294 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.000873 AC: 3 AN: 3438

East Asian (EAS) AF: 0.0143 AC: 73 AN: 5118

South Asian (SAS) AF: 0.00 AC: 0 AN: 4640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000164 AC: 11 AN: 67272

Other (OTH) AF: 0.00346 AC: 7 AN: 2024

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00551

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		8.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.89
gMVP		0.89
Mutation Taster		=93/7	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3751353;

hg19: chr13-24895134;