11-63999646-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_014067.4(MACROD1):c.782C>T(p.Ser261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,457,012 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: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MACROD1
NM_014067.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.35

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACROD1	NM_014067.4 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 6 of 11	ENST00000255681.7	NP_054786.2	Q9BQ69
MACROD1	NM_001411019.1 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 6 of 10		NP_001397948.1
MACROD1	XM_011544970.3 link	c.752C>T	p.Ser251Leu	missense_variant	Exon 5 of 9		XP_011543272.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MACROD1	ENST00000255681.7 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 6 of 11	1	NM_014067.4	ENSP00000255681.6	Q9BQ69
MACROD1	ENST00000675777.1 link	c.782C>T	p.Ser261Leu	missense_variant	Exon 6 of 10			ENSP00000502549.1	A0A6Q8PH91
OTUB1	ENST00000535715.5 link	c.779-1810G>A		intron_variant	Intron 8 of 9	5		ENSP00000440211.1	F5GYJ8
MACROD1	ENST00000543422.5 link	n.346C>T		non_coding_transcript_exon_variant	Exon 4 of 6	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000174

AC:

AN:

229652

Hom.:

AF XY:

0.0000237

AC XY:

AN XY:

126524

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:

0.0000397

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1457012

Hom.:

Cov.:

AF XY:

0.00000966

AC XY:

AN XY:

724504

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:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.782C>T (p.S261L) alteration is located in exon 6 (coding exon 6) of the MACROD1 gene. This alteration results from a C to T substitution at nucleotide position 782, causing the serine (S) at amino acid position 261 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

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.9

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.58

MVP

0.55

MPC

0.79

ClinPred

1.0

GERP RS

3.8

Varity_R

0.57

gMVP

0.75

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over