rs370776611

Variant names:

• chr11-63999371-A-G
• rs370776611
• NM_014067.4:c.851T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-63999371-A-G
• chr11-63999371-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014067.4(MACROD1):​c.851T>C​(p.Leu284Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,593,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: MACROD1 NM_014067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

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.851T>C	p.Leu284Pro	missense	Exon 8 of 11	NP_054786.2
	MACROD1	NM_001411019.1		c.851T>C	p.Leu284Pro	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.851T>C	p.Leu284Pro	missense	Exon 8 of 11	ENSP00000255681.6	Q9BQ69
	MACROD1	ENST00000909130.1		c.868T>C	p.Trp290Arg	missense	Exon 8 of 11	ENSP00000579189.1
	MACROD1	ENST00000675777.1		c.851T>C	p.Leu284Pro	missense	Exon 8 of 10	ENSP00000502549.1	A0A6Q8PH91

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000326 AC: 7 AN: 214484 AF XY: 0.0000339

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000629

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000541 AC: 78 AN: 1441582 Hom.: 0 Cov.: 31 AF XY: 0.0000461 AC XY: 33 AN XY: 716270

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 43404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39344

South Asian (SAS) AF: 0.00 AC: 0 AN: 84210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4872

European-Non Finnish (NFE) AF: 0.0000642 AC: 71 AN: 1106768

Other (OTH) AF: 0.000117 AC: 7 AN: 59716

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74288

African (AFR) AF: 0.0000483 AC: 2 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68006

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000568 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000583 AC: 7

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	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.68	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.80
MVP		0.47
MPC		0.99
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.96
gMVP		0.85
Mutation Taster		=36/64	disease causing

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: rs370776611; hg19: chr11-63766843;