Variant 11-63998972-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014067.4(MACROD1):c.956C>T(p.Pro319Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 1,454,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

MACROD1
NM_014067.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

Variant links:

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]

MACROD1 links:

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]

OTUB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24182817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MACROD1	NM_014067.4 linkuse as main transcript	c.956C>T	p.Pro319Leu	missense_variant	9/11	ENST00000255681.7
MACROD1	NM_001411019.1 linkuse as main transcript	c.956C>T	p.Pro319Leu	missense_variant	9/10
MACROD1	XM_011544970.3 linkuse as main transcript	c.926C>T	p.Pro309Leu	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROD1	ENST00000255681.7 linkuse as main transcript	c.956C>T	p.Pro319Leu	missense_variant	9/11	1	NM_014067.4	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000871

AC:

AN:

229612

Hom.:

AF XY:

0.00000795

AC XY:

AN XY:

125864

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:

0.0000199

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000894

AC:

AN:

1454190

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723056

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:

0.0000108

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000830

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2024

The c.956C>T (p.P319L) alteration is located in exon 9 (coding exon 9) of the MACROD1 gene. This alteration results from a C to T substitution at nucleotide position 956, causing the proline (P) at amino acid position 319 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.15

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.86

M_CAP

Benign

0.042

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.092

Sift

Uncertain

0.010

Sift4G

Uncertain

0.019

Polyphen

0.60

Vest4

0.42

MutPred

0.40

Loss of disorder (P = 0.0326);

MVP

0.36

MPC

0.85

ClinPred

0.99

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.45

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over