dbSNP rs1255072644: COMMD1:p.Leu6Ile (chr2-61905694-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152516.4(COMMD1):c.16C>A(p.Leu6Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,421,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. L6F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

COMMD1
NM_152516.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.221

Variant links:

Genes affected

COMMD1 (HGNC:23024): (copper metabolism domain containing 1) Enables several functions, including phosphatidylinositol-3,4-bisphosphate binding activity; phospholipid binding activity; and protein homodimerization activity. Involved in several processes, including Golgi to plasma membrane transport; negative regulation of protein localization to cell surface; and regulation of cellular protein metabolic process. Acts upstream of or within negative regulation of NF-kappaB transcription factor activity. Located in cytosol; endosome; and nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

COMMD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057078898).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COMMD1	NM_152516.4 link	c.16C>A	p.Leu6Ile	missense_variant	Exon 1 of 3	ENST00000311832.6	NP_689729.1	Q8N668-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COMMD1	ENST00000311832.6 link	c.16C>A	p.Leu6Ile	missense_variant	Exon 1 of 3	1	NM_152516.4	ENSP00000308236.5		Q8N668-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000501

AC:

AN:

199498

Hom.:

AF XY:

0.00000928

AC XY:

AN XY:

107708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000422

AC:

AN:

1421708

Hom.:

Cov.:

AF XY:

0.00000569

AC XY:

AN XY:

702622

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000550

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000315

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.6

DANN

Benign

0.86

DEOGEN2

Benign

0.13

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.31

M_CAP

Benign

0.0063

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.46

PROVEAN

Benign

0.15

REVEL

Benign

0.055

Sift

Benign

0.49

Sift4G

Benign

0.42

Polyphen

0.0070

Vest4

0.26

MutPred

0.20

Gain of catalytic residue at L6 (P = 0.0114);

MVP

0.21

MPC

0.33

ClinPred

0.035

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.036

gMVP

0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over