11-63999694-C-T

Variant names:

• chr11-63999694-C-T
• rs199876740
• NM_014067.4:c.734G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_014067.4(MACROD1):​c.734G>A​(p.Ser245Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000529 in 1,609,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: MACROD1 NM_014067.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255
• Publications: 2 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04843071).

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.734G>A	p.Ser245Asn	missense	Exon 6 of 11	NP_054786.2
	MACROD1	NM_001411019.1		c.734G>A	p.Ser245Asn	missense	Exon 6 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.734G>A	p.Ser245Asn	missense	Exon 6 of 11	ENSP00000255681.6	Q9BQ69
	MACROD1	ENST00000909130.1		c.734G>A	p.Ser245Asn	missense	Exon 6 of 11	ENSP00000579189.1
	MACROD1	ENST00000675777.1		c.734G>A	p.Ser245Asn	missense	Exon 6 of 10	ENSP00000502549.1	A0A6Q8PH91

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000302 AC: 70 AN: 231494 AF XY: 0.000251

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: 0.000249

Gnomad NFE exome AF: 0.000609

Gnomad OTH exome AF: 0.000533

GnomAD4 exome AF: 0.000559 AC: 815 AN: 1456852 Hom.: 0 Cov.: 32 AF XY: 0.000555 AC XY: 402 AN XY: 724530

African (AFR) AF: 0.0000599 AC: 2 AN: 33408

American (AMR) AF: 0.0000224 AC: 1 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85674

European-Finnish (FIN) AF: 0.000331 AC: 17 AN: 51298

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4920

European-Non Finnish (NFE) AF: 0.000693 AC: 770 AN: 1111206

Other (OTH) AF: 0.000383 AC: 23 AN: 60094

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74478

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000581 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000231 AC: 1

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.000283 AC: 34

ClinVar

ClinVar submissions as Germline

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	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.26
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.057
Sift	Benign	0.16	T
Sift4G	Benign	0.19	T
Polyphen		0.023	B
Vest4		0.099
MVP		0.14
MPC		0.78
ClinPred		0.056	T
GERP RS		2.8
Varity_R		0.14
gMVP		0.32
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199876740; hg19: chr11-63767166; COSMIC: COSV55363781; COSMIC: COSV55363781;