chr4-47463645-G-A

Variant names:

• chr4-47463645-G-A
• rs1375054019
• NM_017845.5:c.7C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017845.5(COMMD8):​c.7C>T​(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign 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. P3A) 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: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.349
• 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):

LOC107986277 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06414011).

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.7C>T	p.Pro3Ser	missense	Exon 1 of 5	NP_060315.1	Q9NX08
	COMMD8	NM_001329668.2		c.7C>T	p.Pro3Ser	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.7C>T	p.Pro3Ser	missense	Exon 1 of 5	ENSP00000370984.4	Q9NX08
	COMMD8	ENST00000952424.1		c.7C>T	p.Pro3Ser	missense	Exon 1 of 6	ENSP00000622483.1
	COMMD8	ENST00000860334.1		c.7C>T	p.Pro3Ser	missense	Exon 1 of 5	ENSP00000530393.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396742 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688822

African (AFR) AF: 0.00 AC: 0 AN: 31450

American (AMR) AF: 0.00 AC: 0 AN: 35544

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 35630

South Asian (SAS) AF: 0.00 AC: 0 AN: 79064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5468

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078180

Other (OTH) AF: 0.00 AC: 0 AN: 57884

GnomAD4 genome Cov.: 34

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	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.35
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.018
Sift	Benign	0.30	T
Sift4G	Benign	0.59	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.41		Loss of glycosylation at P3 (P = 0.0225)
MVP		0.30
MPC		0.14
ClinPred		0.26	T
GERP RS		1.4
PromoterAI		-0.34	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.080
gMVP		0.29
Mutation Taster		=91/9	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: rs1375054019; hg19: chr4-47465662;