11-36280819-C-A

Variant names:

• chr11-36280819-C-A
• rs201813122
• NM_014186.4:c.70G>T

Variant summary

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

The NM_014186.4(COMMD9):​c.70G>T​(p.Val24Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V24L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: COMMD9 NM_014186.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88
• Publications: 0 publications found

Genes affected

COMMD9 (HGNC:25014): (COMM domain containing 9) Predicted to be involved in sodium ion transport. Predicted to act upstream of or within cholesterol homeostasis. Located in Golgi apparatus; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014186.4. 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
	COMMD9	NM_014186.4	MANE Select	c.70G>T	p.Val24Phe	missense	Exon 2 of 6	NP_054905.2	Q53FR9
	COMMD9	NM_001307937.2		c.43G>T	p.Val15Phe	missense	Exon 3 of 7	NP_001294866.1
	COMMD9	NM_001307932.2		c.70G>T	p.Val24Phe	missense	Exon 2 of 5	NP_001294861.1	E9PJ95

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMMD9	ENST00000263401.10	TSL:1 MANE Select	c.70G>T	p.Val24Phe	missense	Exon 2 of 6	ENSP00000263401.5	Q9P000-1
	COMMD9	ENST00000877672.1		c.70G>T	p.Val24Phe	missense	Exon 2 of 6	ENSP00000547731.1
	COMMD9	ENST00000532705.1	TSL:2	c.70G>T	p.Val24Phe	missense	Exon 2 of 5	ENSP00000435599.1	E9PJ95

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713002

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32340

American (AMR) AF: 0.00 AC: 0 AN: 40654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 82642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1098340

Other (OTH) AF: 0.00 AC: 0 AN: 59068

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.78	P
Vest4		0.85
MutPred		0.76		Loss of ubiquitination at K21 (P = 0.1306)
MVP		0.17
MPC		0.84
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.89
gMVP		0.81
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201813122; hg19: chr11-36302369;