chr11-63999694-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014067.4(MACROD1):​c.734G>T​(p.Ser245Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,852 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S245N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MACROD1 NM_014067.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.255
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>T	p.Ser245Ile	missense	Exon 6 of 11	NP_054786.2
	MACROD1	NM_001411019.1		c.734G>T	p.Ser245Ile	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>T	p.Ser245Ile	missense	Exon 6 of 11	ENSP00000255681.6	Q9BQ69
	MACROD1	ENST00000909130.1		c.734G>T	p.Ser245Ile	missense	Exon 6 of 11	ENSP00000579189.1
	MACROD1	ENST00000675777.1		c.734G>T	p.Ser245Ile	missense	Exon 6 of 10	ENSP00000502549.1	A0A6Q8PH91

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456852 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724530

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44582

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

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

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4920

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111206

Other (OTH) AF: 0.00 AC: 0 AN: 60094

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.26
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.53		Loss of disorder (P = 0.0057)
MVP		0.42
MPC		0.92
ClinPred		0.96	D
GERP RS		2.8
Varity_R		0.65
gMVP		0.51
Mutation Taster		=73/27	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;