Variant 11-63999533-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014067.4(MACROD1):c.814T>G(p.Phe272Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MACROD1
NM_014067.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.37

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MACROD1	NM_014067.4 linkuse as main transcript	c.814T>G	p.Phe272Val	missense_variant	7/11	ENST00000255681.7
MACROD1	NM_001411019.1 linkuse as main transcript	c.814T>G	p.Phe272Val	missense_variant	7/10
MACROD1	XM_011544970.3 linkuse as main transcript	c.784T>G	p.Phe262Val	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MACROD1	ENST00000255681.7 linkuse as main transcript	c.814T>G	p.Phe272Val	missense_variant	7/11	1	NM_014067.4	P4
MACROD1	ENST00000675777.1 linkuse as main transcript	c.814T>G	p.Phe272Val	missense_variant	7/10			A2
OTUB1	ENST00000535715.5 linkuse as main transcript	c.778+1765A>C		intron_variant		5
MACROD1	ENST00000543422.5 linkuse as main transcript	n.378T>G		non_coding_transcript_exon_variant	5/6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000137

AC:

AN:

1455478

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723570

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Oct 12, 2021

The c.814T>G (p.F272V) alteration is located in exon 7 (coding exon 7) of the MACROD1 gene. This alteration results from a T to G substitution at nucleotide position 814, causing the phenylalanine (F) at amino acid position 272 to be replaced by a valine (V). 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

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.19

Eigen

Benign

-0.0095

Eigen_PC

Benign

0.022

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.038

Vest4

0.55

MutPred

0.86

Loss of sheet (P = 0.1907);

MVP

0.40

MPC

0.33

ClinPred

0.99

GERP RS

3.6

Varity_R

0.91

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over