NM_014067.4:c.844A>G

Variant names:

• chr11-63999378-T-C
• NM_014067.4:c.844A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014067.4(MACROD1):​c.844A>G​(p.Ile282Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MACROD1 NM_014067.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.991
• Publications: 0 publications found

Genes affected

MACROD1 (HGNC:29598): (mono-ADP ribosylhydrolase 1) Enables ADP-ribosylglutamate hydrolase activity and deacetylase activity. Involved in cellular response to DNA damage stimulus; peptidyl-glutamate ADP-deribosylation; and purine nucleoside metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

OTUB1 (HGNC:23077): (OTU deubiquitinase, ubiquitin aldehyde binding 1) The product of this gene is a member of the OTU (ovarian tumor) superfamily of predicted cysteine proteases. The encoded protein is a highly specific ubiquitin iso-peptidase, and cleaves ubiquitin from branched poly-ubiquitin chains but not from ubiquitinated substrates. It interacts with another ubiquitin protease and an E3 ubiquitin ligase that inhibits cytokine gene transcription in the immune system. It is proposed to function in specific ubiquitin-dependent pathways, possibly by providing an editing function for polyubiquitin chain growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04952264).
• BP6: Variant 11-63999378-T-C is Benign according to our data. Variant chr11-63999378-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3292512.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014067.4. 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
	MACROD1	NM_014067.4	MANE Select	c.844A>G	p.Ile282Val	missense	Exon 8 of 11	NP_054786.2
	MACROD1	NM_001411019.1		c.844A>G	p.Ile282Val	missense	Exon 8 of 10	NP_001397948.1	A0A6Q8PH91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MACROD1	ENST00000255681.7	TSL:1 MANE Select	c.844A>G	p.Ile282Val	missense	Exon 8 of 11	ENSP00000255681.6	Q9BQ69
	MACROD1	ENST00000675777.1		c.844A>G	p.Ile282Val	missense	Exon 8 of 10	ENSP00000502549.1	A0A6Q8PH91
	MACROD1	ENST00000909128.1		c.850A>G	p.Ile284Val	missense	Exon 8 of 11	ENSP00000579187.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely benign

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	0.057
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.61
DEOGEN2	Benign	0.035	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.33	N
PhyloP100		0.99
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.13	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0020	B
Vest4		0.16
MutPred		0.66		Loss of catalytic residue at L287 (P = 0.239)
MVP		0.092
MPC		0.19
ClinPred		0.039	T
GERP RS		3.0
Varity_R		0.047
gMVP		0.20
Mutation Taster		=92/8	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

hg19: chr11-63766850;