4-47463605-G-A

Variant names:

• chr4-47463605-G-A
• rs1002034383
• NM_017845.5:c.47C>T

Variant summary

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

The NM_017845.5(COMMD8):​c.47C>T​(p.Pro16Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000717 in 1,394,528 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. P16R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: COMMD8 NM_017845.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.75
• Publications: 0 publications found

Genes affected

COMMD8 (HGNC:26036): (COMM domain containing 8) The protein encoded by this gene binds coiled-coil domain-containing protein 22 (CCDC22), and this complex can regulate the turnover of I-kappa-B and the activation of NF-kappa-B. [provided by RefSeq, Jul 2016]

ENSG00000282904 (HGNC:58765):

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, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017845.5. 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
	COMMD8	NM_017845.5	MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	NP_060315.1	Q9NX08
	COMMD8	NM_001329668.2		c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	NP_001316597.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COMMD8	ENST00000381571.6	TSL:1 MANE Select	c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	ENSP00000370984.4	Q9NX08
	COMMD8	ENST00000952424.1		c.47C>T	p.Pro16Leu	missense	Exon 1 of 6	ENSP00000622483.1
	COMMD8	ENST00000860334.1		c.47C>T	p.Pro16Leu	missense	Exon 1 of 5	ENSP00000530393.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394528 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687776

⚠️ 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: 31426

American (AMR) AF: 0.00 AC: 0 AN: 35580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25088

East Asian (EAS) AF: 0.00 AC: 0 AN: 35656

South Asian (SAS) AF: 0.00 AC: 0 AN: 79056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4938

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078146

Other (OTH) AF: 0.0000173 AC: 1 AN: 57820

⚠️ 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.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.75		Gain of loop (P = 0.0051)
MVP		0.63
MPC		0.52
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.30
gMVP		0.53
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1002034383; hg19: chr4-47465622;