11-63999694-C-T

Position:

• chr11-63999694-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 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. 12/21 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

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04843071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACROD1	NM_014067.4	c.734G>A	p.Ser245Asn	missense_variant	6/11	ENST00000255681.7
MACROD1	NM_001411019.1	c.734G>A	p.Ser245Asn	missense_variant	6/10
MACROD1	XM_011544970.3	c.704G>A	p.Ser235Asn	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACROD1	ENST00000255681.7	c.734G>A	p.Ser245Asn	missense_variant	6/11	1	NM_014067.4	P4
MACROD1	ENST00000675777.1	c.734G>A	p.Ser245Asn	missense_variant	6/10			A2
OTUB1	ENST00000535715.5	c.779-1762C>T		intron_variant		5
MACROD1	ENST00000543422.5	n.298G>A		non_coding_transcript_exon_variant	4/6	3

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

GnomAD3 exomes AF: 0.000302 AC: 70 AN: 231494 Hom.: 0 AF XY: 0.000251 AC XY: 32 AN XY: 127626

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: 0.000249

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

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000331

Gnomad4 NFE exome AF: 0.000693

Gnomad4 OTH exome AF: 0.000383

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

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000570 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2021

The c.734G>A (p.S245N) alteration is located in exon 6 (coding exon 6) of the MACROD1 gene. This alteration results from a G to A substitution at nucleotide position 734, causing the serine (S) at amino acid position 245 to be replaced by an asparagine (N). 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	0.12
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
MutationTaster	Benign	0.88	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs199876740; hg19: chr11-63767166; COSMIC: COSV55363781; COSMIC: COSV55363781;